|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• calcification of the fibrous capsule surrounding the muzzle vibrissae is not observed at 20 weeks of age, however, at one year of age, some calcification is present
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• calcification of the fibrous capsule surrounding the muzzle vibrissae is not observed at 20 weeks of age, however, at one year of age, some calcification is present
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• diethylnitrosamine (DEN)-challenged mice exhibit decreased survival compared with similarly treated wild-type mice
|
|
• LPS-challenged mice exhibit decreased survival compared with similarly treated wild-type mice
|
|
• diethylnitrosamine (DEN)-challenged mice exhibit decreased survival compared with similarly treated wild-type mice
|
|
• LPS-challenged mice exhibit decreased survival compared with similarly treated wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• no defect in the closure of the ductus venosus is seen unlike in mice homozygous for Ahrtm3Bra
|
|
• exposure to 100 ug 2,3,7,8-tetrachlorodibenzo-p-dioxin failed to induce hepatomegaly, or Cyp1a2 expression, only weakly induced Cyp1a1 expression, partially induced Cyp1b1 expression, and resulted in significantly less liver damage compared to homozygous mice lacking the cre transgene
• however, exposure to 100 ug 2,3,7,8-tetrachlorodibenzo-p-dioxin did induce thymic involution similar to homozygous mice lacking the cre transgene
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice exhibit elevated liver, plasma, stool, and biliary levels of desmosterol
• mice exhibit slightly elevated lanosterol levels in the liver
• however, circulating levels of cholesterol are normal, sterol levels in the brains show no differences in cholesterol or desmosterol levels, and no changes in the levels of stool cholesterol are seen
|
 |
• hepatic cholesterol levels are slightly decreased in females
|
|
• liver shows elevated desmosterol level and slightly elevated lanosterol levels
• however, no differences are seen in liver cell morphology or hepatic lipid accumulation
|
|
|
• hepatic cholesterol levels are slightly decreased in females
|
|
• biliary desmosterol level is increased
• however, no differences in levels of biliary cholesterol, bile acids or biliary phospholipids are seen
|
|
• stool desmosterol level is increased
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice show no changes in parameters of glucose homeostasis, with unaltered glucose and insulin tolerance, unaltered plasma cholesterol levels, and no changes in hepatic triglyceride secretion rates
|
|
• desmosterol secretion into bile is decreased
• 7-DHC excretion into bile is increased
|
 |
• males show a small increase in levels of biliary bile acids
• however, phospholipid levels do not differ in bile or plasma
|
|
• mice exhibit an elevation of plasma levels of 7-dehydrocholesterol (DHC) and its isomer 8-DHC, and of lathosterol, and a decrease in plasma desmosterol levels
• females only show an increase in 7-dehydrodesmosterol (DHD), the immediate precursor to desmosterol
• males only show an increase in 24-dehydrolathosterol levels
• mice show altered sterol profiles in the liver, with elevated 7-DHC and 8-DHC levels
• males only show elevated levels of lathosterol and DHD in the liver
• however, no changes in levels of vitamin D3 or 25OH-vitamin D3 are seen and sterol profiles are unaltered in the brain
• the biliary sterol profile more closely mirrors the plasma sterol levels than the hepatic sterol levels
|
|
• females only show decreased levels of cholesterol and desmosterol in the liver
|
|
• females only show decreased levels of cholesterol and desmosterol in the liver
|
|
• the cholesterol content of bile is similar to controls, but 7-DHC and 8-DHC in bile are elevated
• bile shows decreased desmosterol, increased 7-dehydrodesmosterol and lathosterol, but no difference in lanosterol
|
| N |
• body weight, percent body fat and lean mass (except for males at 10-14 weeks of age) are similar to wild-type
|
|
|
• males show a slightly lower lean body mass at 10-14 weeks of age
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Smith-Lemli-Opitz syndrome | DOID:14692 |
OMIM:270400 |
J:303316 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 5 out of 13 mice exhibit calcification of the fibrous capsule surrounding the muzzle vibrissae occurs at 20 weeks of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• none of the control heterozygotes died within the 100 days of the observation period
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice are born alive and survive for at least several weeks but die of fatal bleeding as a result of bleeding diathesis, injury and pregnancy
• when kept separately without mating, female mice survive significantly longer than male mice
• male mice begin to die from day 27 after birth, and all males die within 80 days after birth
• female mice begin to die from day 39 after birth and 7 out of 11 (63.6%) survive longer than 100 days, unless they become pregnant
|
|
|
• pregnancy causes fatal vaginal and uterine bleeding
|
|
|
• dissection of pregnant female mice just after death revealed uterine bleeding
|
|
• dissection of pregnant female mice just after death revealed vaginal bleeding
|
|
• at 9 weeks of age, massive subcutaneous bleeding is noted even before death
|
|
• activities of vitamin K-dependent coagulation factors II and IX are significantly decreased relative to wild-type controls
|
|
• mice exhibit a bleeding diathesis and continue to bleed for >30 minutes after tail incision
• however, the platelet count is not significantly altered, suggesting that increased bleeding time is due to defective secondary coagulation
|
|
• at 9 weeks of age, massive subcutaneous bleeding is noted even before death
|
|
|
• dissection of pregnant female mice just after death revealed uterine bleeding
|
|
• dissection of pregnant female mice just after death revealed vaginal bleeding
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice subjected to oxygen-induced retinopathy and with treated dimethyloxaloylglycine fail to exhibit an improvement in percent avascular retina and tortuosity ratio compared with similarly treated wildtype mice
|
| N |
• under normoxic conditions, mice exhibit normal retinal development
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
The leucine metabolite 2-ketoisocaproate induces liver steatosis in Hmgcltm2Gam/Hmgcltm2Gam Speer6-ps1Tg(Alb-cre)21Mgn/0 mice
|
• all mice die between 3 and 5 weeks following spontaneous episodes, or crises, of progressive lethargy, hypoglycemia and hyperammonia
• however, mice fed a low protein diet plus 10% glucose in drinking water exhibit diminished occurrence of crises
|
| N |
• mice exhibit normal peroxisome-related metabolites
|
|
• elevated levels of leucine-related metabolites in stressed mice (following injection of KIC or during spontaneous crises)
• increased plasma acylcarnities in stressed mice
|
|
• before death
• in mice treated with the leucine metabolite 2-ketoisocaproate (KIC)
• however, hyperammonemia is improved by carglumate treatment
|
|
• before death
• in mice treated with the leucine metabolite 2-ketoisocaproate (KIC)
|
|
• reduced gluconeogenesis in hepatocytes
|
|
• dilated in hepatocytes
|
|
• undetectable ketogenesis from octanoate in hepatocytes
• reduced gluconeogenesis in hepatocytes
|
|
• dilated in hepatocytes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice exhibit slower plasma clearance of triglycerides and VLDL compared with wild-type mice
• however, plasma cholesterol levels are normal
|
|
• 2-fold
|
|
• hepatocytes exhibit decreased VLDL binding, uptake, and degradation compared with wild-type cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• all mice are dead by 60 weeks
|
|
• the first mice die at P14 and more than half of mice die by P21
|
| N |
• mice exhibit normal liver structure at P0
|
|
• 3 times in controls
|
|
• at P7, mice exhibit increased immature cholangiocyte-like and oval cells that becomes massive at P10 especially in periductal and intraductal locations
• mild hepatocholangiocellular hyperplasia at P21
|
|
• massive
|
|
• 5 times greater than in control mice at P14
|
|
• combined hepatocellular and cholangiocarcinomas, increased hepatocellular carcinoma, liver adenoma incidence or cholangiocarcinoma in 8 of 10 mice surviving beyond P21 by age 15 weeks
• combined hepatocellular and cholangiocarcinomas in 13 of 22 mice at week 60
• with lung metastasis after 40 weeks of age
|
|
• intrahepatic cholangiocellular carcinoma in 8 of 10 mice surviving beyond P21 by age 15 weeks
• in 2 of 22 mice at week 60
|
|
• in mice surviving beyond P21 by age 15 weeks
• in 4 of 22 mice at week 60
|
|
• in mice surviving beyond P21 by age 15 weeks
|
|
• cholangiocytes proliferation is increased 4 times compared with controls
• however, there is no increase in apoptosis
|
|
• combined hepatocellular and cholangiocarcinomas, increased hepatocellular carcinoma, liver adenoma incidence or cholangiocarcinoma in 8 of 10 mice surviving beyond P21 by age 15 weeks
• combined hepatocellular and cholangiocarcinomas in 13 of 22 mice at week 60
• with lung metastasis after 40 weeks of age
|
|
• intrahepatic cholangiocellular carcinoma in 8 of 10 mice surviving beyond P21 by age 15 weeks
• in 2 of 22 mice at week 60
|
|
• in mice surviving beyond P21 by age 15 weeks
• in 4 of 22 mice at week 60
|
|
• in mice surviving beyond P21 by age 15 weeks
|
|
• due to enlarged liver
|
|
• 3 times in controls
|
|
• at P7, mice exhibit increased immature cholangiocyte-like and oval cells that becomes massive at P10 especially in periductal and intraductal locations
• mild hepatocholangiocellular hyperplasia at P21
|
|
• massive
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• elevation in plasma total cholesterol that is associated with more than 3-fold increase in free cholesterol
• high increase in plasma free cholesterol/plasma total cholesterol ratio
• develop severe hypercholesterolemia on an atherogenic diet due to an accumulation of free cholesterol-rich, VLDL-sized particles
• hepatic content of free and esterified cholesterol is normal
|
|
• marked elevation of HDL cholesterol with abnormally large HDL particles
|
|
• on an atherogenic diet, IL-6 plasma levels are 6.6-fold greater than in wild-type
|
|
• atherosclerosis is enhanced 32-fold compared to controls, when fed an atherogenic (high-fat, high-cholesterol, and cholic acid-containing) diet
|
|
• on an atherogenic diet, IL-6 plasma levels are 6.6-fold greater than in wild-type
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Ahrb-1/Ahrb-1 Aiptm2.1Bra/Aiptm2.1Bra Speer6-ps1Tg(Alb-cre)21Mgn/0 mice are resistant to dioxin-induced hepatic damage
|
• doxin-treated mice do not exhibit an increase in serum alanine transaminase unlike similarly treated Aiptm2.1Bra homozygotes
|
|
• doxin-treated mice do not exhibit an increase in serum alanine transferase and are resistant to induced hepatic damage unlike similarly treated Aiptm2.1Bra homozygotes
• however, doxin-treated mice exhibit increased liver and thymus weight similar to wild-type mice
|
|
• in 1 of 8 mice
|
|
• at 8 weeks
|
|
• in 1 of 8 mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in fasting mice
|
|
• at 22 weeks, but not 9 weeks, in male mice when normalized to body weight
|
|
• at 22 weeks, but not 9 weeks, in male mice when normalized to body weight
|
|
• during the dark cycle in male mice at 22 weeks
|
|
• slight in male mice, but not female mice
|
|
• hepatocytes exhibit decreased relative lipid synthesis compared with control cells
|
|
• fatty acid oxidation in the liver of male mice is increased compared to in control mice
|
|
• in fasting mice
|
|
• at 9 weeks, but not 31 weeks, in male mice
|
|
• at 31 weeks in male mice
|
|
• at 31 weeks in male mice
|
|
• at 31 weeks in male mice
|
|
• at 31 weeks in male mice
|
|
• induced by age or palmitic acid
• however, mice exhibit normal susceptibility to high fat diet-induced steatosis
|
|
• at 6, 9 and 20 weeks
|
|
• at 6, 9 and 20 weeks
|
|
• lean mass and content at 20 weeks in male mice, but not female mice
|
|
• slight in male mice, but not female mice
|
|
• slight in female and male mice fed standard chow
• in male mice fed a high fat diet
|
|
• fatty acid oxidation in the liver of male mice is increased compared to in control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• liver weight to body weight ratio is significantly increased at 12 weeks of age
• however, body weight is normal
|
|
• hepatic glycogen levels are significantly increased at 8 weeks of age
|
|
• hepatic triglyceride levels are significantly increased at 12 weeks of age
|
|
• Oil red O staining revealed lipid accumulation in liver tissues at 8 weeks of age
|
|
• collagen deposition is significantly increased at 8 weeks of age, suggesting liver fibrosis
• however, no severe hepatomegaly or tumorigenesis are observed over a period of 4 months after birth
|
|
• after 24 h of fasting, liver tissue ketone body levels are significantly lower than those in wild-type controls
• however, liver tissue ketone body levels are normal under fed conditions
|
|
• protein levels of the autophagy markers p62 and LC3 are increased in the liver at 8 weeks of age, indicating impaired autophagosome maturation
• TEM analysis revealed a significantly increased number of autophagosomes surrounding lipid droplets in hepatocytes at 12 weeks of age
|
|
• after 24 h of fasting, total serum ketone body levels are significantly lower than those in wild-type controls
• however, total serum ketone body levels are normal under fed conditions
|
|
• hepatic glycogen levels are significantly increased at 8 weeks of age
|
|
• hepatic triglyceride levels are significantly increased at 12 weeks of age
|
|
• protein levels of the autophagy markers p62 and LC3 are increased in the liver at 8 weeks of age, indicating impaired autophagosome maturation
• TEM analysis revealed a significantly increased number of autophagosomes surrounding lipid droplets in hepatocytes at 12 weeks of age
|
|
• liver weight to body weight ratio is significantly increased at 12 weeks of age
• however, body weight is normal
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• resistant to high carbohydrate and high-sucrose very low-fat, but not high fat, diet-induced obesity
|
|
• reduced by 51% in mice on a high-sucrose very low-fat diet compared to diet matched controls
|
|
• on a high carbohydrate diet weights of the gonadal, retroperitioneal, and inguinal fat pads are reduced by about 49% - 59% compared to controls lacking the cre transgene
|
|
• reduced weight on a high carbohydrate diet compared to diet matched controls
|
|
• reduced weight on a high carbohydrate diet compared to diet matched controls
|
|
• reduced weight on a high carbohydrate diet compared to diet matched controls
|
| N |
• unlike global null mice, no difference is seen in plasma glucose and insulin levels, glucose clearance or insulin sensitivity between liver knockout mice and controls on a high carbohydrate diet
|
|
• resistant to high carbohydrate and high-sucrose very low-fat, but not high fat, diet-induced obesity
|
|
• reduced in mice on a high-sucrose very low-fat diet compared to diet matched controls
• but not in mice on high carbohydrate, high fat, or chow diet
• supplementing the high-sucrose very low-fat diet with oleate prevents the decrease in plasma glucose levels
|
|
• impaired production of glucose from pyruvate in mice fed a high-sucrose very low-fat diet
|
|
• reduced glycogen levels in the liver in mice on a high-sucrose very low-fat diet compared to diet matched controls
• supplementing the diet with oleate prevents the decrease in hepatic glycogen levels
|
|
• 85% decrease in hepatic lipogenesis in mice on a high carbohydrate diet
• however, cholesterol synthesis is unaffected
|
|
• develops in mice on a high-sucrose very low-fat diet, probably due to increases in HDL and LDL cholesterol
|
|
• in mice on a high carbohydrate diet compared to diet-matched controls
• however, levels are similar to controls in mice on a chow or high fat diet
|
|
• significant reduction in mice on a high carbohydrate or a high-sucrose very low-fat diet compared to diet-matched controls
|
|
• on a high carbohydrate or diet high-sucrose very low-fat diet, liver triglyceride levels are reduced by 69% or 49%, respectively, compared to controls
• fasted mice refed a fat free high carbohydrate diet have lower liver levels of SCD1 products including palmitoleate and oleate
• supplementing the diet with triolein reduces the decrease in liver triglyceride levels
|
|
• reduced glycogen levels in the liver in mice on a high-sucrose very low-fat diet compared to diet matched controls
• supplementing the diet with oleate prevents the decrease in hepatic glycogen levels
|
|
• on a high carbohydrate or diet high-sucrose very low-fat diet, liver triglyceride levels are reduced by 69% or 49%, respectively, compared to controls
• fasted mice refed a fat free high carbohydrate diet have lower liver levels of SCD1 products including palmitoleate and oleate
• supplementing the diet with triolein reduces the decrease in liver triglyceride levels
|
|
• resistant to high carbohydrate and high-sucrose very low-fat, but not high fat, diet-induced fatty liver development
|
|
• block in carbohydrate-induce hepatic lipogenesis
• a high-sucrose very low-fat diet fails to increase the rate of triglyceride secretion, unlike in controls
|
| N |
• unlike global null mice, no difference in food intake is seen in mice on a chow diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increase in hepatocyte apoptosis, particularly at 5 weeks
|
|
• 5-week-old mice show an increase in hepatocyte proliferation
|
|
• livers show inflammatory cell infiltration
• expansion of liver macrophages
• elevation of intrahepatic IL-1beta, IL-6, and TNF-alpha levels
|
|
• 12-month old mice show signs of liver disease, including fatty change, necrosis, inflammatory cell infiltration, and increased liver injury with impaired liver damage response
|
|
• ratio of liver weight to body weight is slightly increased in 5-week-old mice
|
|
• hepatocytes show aberrant chromosome polyploidy during postnatal liver development
|
|
• primary hepatocytes show higher proportions of octoploid hepatocytes but almost no diploid hepatocytes after weaning compared to wild-type hepatocytes which show increased tetraploid and octoploid and lower diploid after weaning, indicating an increase of the hepatic polyploidy population
• the proportion of octoploid hepatocytes gradually increase with age to reach almost 60% at 10 weeks whereas fewer than 20% of octoploid hepatocytes are seen in wild-type mice at the same age
• however, hepatocytes are composed of predominately diploid, with some tetraploid, before weaning as in wild-type hepatocytes and primary mouse embryonic fibroblasts exhibit normal diploidy
• livers show a decrease in the proportion of binucleated hepatocytes starting at 5 weeks of age
• -livers show an increase in the size of mononuclear hepatocytes at 10 weeks of age
• livers show cytomegalic hepatocytes and cytoplasmic vacuolization
|
|
• livers show an increase in nuclear diameters of mononuclear hepatocytes at 10 weeks of age
|
|
• increase in the appearance and expansion of activated hepatic stellate cells
|
|
• livers show extensive steatosis, with increased lipid deposition in the hepatocytes and hepatocyte ballooning, characteristic of nonalcoholic steatohepatitis
|
|
• fibrillar collagen initially seen around the portal veins gradually increases such that many livers are fibrotic at 5 and 10 weeks of age
|
|
• livers show an increase in nuclear diameters of mononuclear hepatocytes at 10 weeks of age
|
|
• increase in hepatocyte apoptosis, particularly at 5 weeks
|
|
• 5-week-old mice show an increase in hepatocyte proliferation
|
|
• ratio of liver weight to body weight is slightly increased in 5-week-old mice
|
|
• alanine aminotransferase (ALT) levels are highly elevated after weaning (5, 10, 20, and 52 weeks of age) but not at 3 weeks of age
|
|
• aspartate aminotransferase (AST) levels are highly elevated after weaning but not at 3 weeks of age
|
|
• mice show increased susceptibility to carbon tetracholoride-induced liver damage, showing more severe liver necrosis and fibrosis and higher ALT, AST, and apoptosis levels, and elevation of intrahepatic fibrogenic cytokines such as IL-6 and TNF-alpha
|
|
• livers show inflammatory cell infiltration
• expansion of liver macrophages
• elevation of intrahepatic IL-1beta, IL-6, and TNF-alpha levels
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pale, swollen mitochondria
|
|
|
• mild hepatic architectural disarray and hepatocellular multinucleation are seen
|
|
|
• many cytosolic lipid droplets and pale swollen mitochondria are seen suggesting metabolic or mitochondrial damage
• multinucleated hepatocytes are seen
|
|
• pale, swollen mitochondria
|
|
|
• 2-fold increase in serum levels of liver-derived transaminases indicative of liver damage
|
|
|
• 76% increase in total liver iron; however, serum iron and total iron binding capacity are similar to controls and no signs of mitochondrial iron overload are detected
• a small subset of hepatocytes particularly cells adjacent to a portal triad or central vein, contain abundant, coarsely granular cytosolic iron deposits
|
|
|
• 50% reduction in hepatic activity of xanthine oxidase; however no change in expression is detected
• about a 20% decrease in hepatic mitochondrial activity of succinate dehydrogenase when normalized to cytochrome C oxidase activity
• about a 90% and 60% decrease in cytosolic aconitate hydratase 1 (Aco1) activity and protein, respectivly, are seen in the liver
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• small but significant reduction in fasted glucose levels
|
|
• following 3-mercaptopicolinic acid treatment
|
| N |
• fasting induced steatosis and glycerol induced glucose production are similar to wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice develop multiple spontaneous hepatocellular carcinomas
|
|
• mice develop multiple spontaneous hepatocellular carcinomas
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| hepatocellular carcinoma | DOID:684 |
OMIM:114550 |
J:238319 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• severe steatosis
|
|
• proliferation of endothelial cells in hepatic blood vessels
|
|
• hepatic vascular angiectasia
|
|
• hepatic vascular angiectasia
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| von Hippel-Lindau disease | DOID:14175 |
OMIM:193300 |
J:97652 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• livers appear histologically normal at 4 - 6 weeks of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• develop massively overgrown livers by 3 months of age (4 out of 4)
|
|
• develop hepatocellular carcinomas (HHCs) by 3 months of age (4 out of 4)
|
|
• develop hepatocellular carcinomas (HHCs) by 3 months of age (4 out of 4)
|
|
• develop massively overgrown livers by 3 months of age (4 out of 4)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 3-month-old mice exhibit liver overgrowth
• however, liver does not show alterations in canalicular morphology, hepatocyte ultrastructure, or hepatic plate thickness, indicating normal hepatocyte polarity
|
|
• 3-month-old mice exhibit increased liver weight relative to total body weight, which is increased in 6-month-old mice and is about 5-fold higher than in controls at 12 months of age
|
|
• liver shows massive enrichment of small cells at portal triads
• liver shows malformation of the portal triads with an increase of ductal structures
• however, the arrangement of hepatic cells close to the central vein appears normal
|
|
• liver shows the presence of fibrotic areas close to portal triads and in the periportal zones
|
|
• 12-month-old mice exhibit numerous liver tumors that have characteristics of both hepatocellular carcinoma and cholangiocarcinoma, possibly representing an intermediate tumor phenotype
• tumors show cells with enlarged, atypical nuclei and irregular arrangements of hepatocytes, and the border between each tumor and normal liver tissue is made up of a collagen-rich capsule
|
|
• 6-month-old livers show enhanced proliferation of immature biliary epithelial cell-like progenitor cells
|
|
• livers show an enrichment of activated myofibroblasts and infiltration with inflammatory macrophages
|
|
• 12-month-old mice exhibit numerous liver tumors that have characteristics of both hepatocellular carcinoma and cholangiocarcinoma, possibly representing an intermediate tumor phenotype
• tumors show cells with enlarged, atypical nuclei and irregular arrangements of hepatocytes, and the border between each tumor and normal liver tissue is made up of a collagen-rich capsule
|
|
• 3-month-old mice exhibit increased liver weight relative to total body weight, which is increased in 6-month-old mice and is about 5-fold higher than in controls at 12 months of age
|
|
• livers show an enrichment of activated myofibroblasts and infiltration with inflammatory macrophages
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• fasting-mediated induction of aminolevulinic acid synthase is decreased in mutants compared to wild-type
|
|
• injection of lead chloride into fasted mice does not alter serum gamma-aminolevulinic acid (ALA) or porphobilinogen (PBG) in contrast to increased levels observed in wild-type
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• progressively coarsened and granular by 8 weeks
• after 6 months, mice develop nodular foci of high-grade dysplasia in the liver
|
|
• swollen, abnormally shaped and with increased spacing or loss of cristae in hepatocyte mitochondria at 2 weeks of age; persistent to a lesser magnitude at 8 weeks
|
|
• at 8 weeks of age
|
|
• focal hepatocyte necrosis at 4 weeks of age
|
|
• higher liver to body weight ratio at 4 to 6 weeks
|
|
• at 8 weeks of age
|
|
• modestly at 2 weeks of age
• however, levels are normal at 4 weeks of age
|
|
• at 2 and 4 weeks of age
• however, levels are normal at 8 weeks of age
|
|
• macro- and micro vesicular steatosis with hepatocyte swelling and minimal inflammation at 2 weeks of age
• reduced at 4 weeks of age
|
|
• pericellular fibrosis at 2 weeks of age
• periportal fibrosis at 4 weeks of age
• bridging fibrosis at 8 weeks of age
|
|
• milky white by 2 weeks of age
• however, livers regain normal color by 4 weeks
|
|
• at 1 year, most mice develop hepatocellular carcinomas with tumor cells that are pleomorphic and often steatotic with frequent mitotic figures and variably anaplastic nuclei
|
|
• prominent bile ductular proliferation at 4 weeks of age
• ductular proliferation at 8 weeks of age
• atypical ductular proliferation at 2 and 4 weeks of age
• cellular proliferation occurs in oval/biliary cells and parenchyma at 4 and 8 weeks of age
|
|
• at 2 weeks of age but decreasing progressively at 4 and 8 weeks of age
|
|
• at 4 and 8 weeks
|
|
• scattered lobular mixed inflammation with focal hepatocyte necrosis and prominent bile ductular proliferation at 4 weeks of age
• increasing portal/perioral and lobular mixed inflammation
|
|
• increased proliferation at 4 and 8 weeks of age
|
|
• at 4 and 8 weeks of age
|
|
• at 8 weeks of age
|
|
• modestly at 2 weeks of age
• however, levels are normal at 4 weeks of age
|
|
• at 2 and 4 weeks of age
• however, levels are normal at 8 weeks of age
|
|
• at 4 and 6 weeks
• however, body weight is normal at 1, 2 and 8 weeks
|
|
• higher liver to body weight ratio at 4 to 6 weeks
|
|
• dilated in hepatocytes with robust lipid deposition at 2 weeks of age; persistent to a lesser magnitude at 8 weeks
|
|
• swollen, abnormally shaped and with increased spacing or loss of cristae in hepatocyte mitochondria at 2 weeks of age; persistent to a lesser magnitude at 8 weeks
|
|
• increased spacing or loss of cristae in hepatocyte mitochondria at 2 weeks of age
|
|
• in hepatocyte mitochondria at 2 weeks of age
|
|
• in hepatocyte at 2 weeks of age
|
|
• in hepatocyte mitochondria at 2 weeks of age
|
|
• at 2 weeks of age but decreasing progressively at 4 and 8 weeks of age
|
|
• at 8 weeks of age
|
|
• focal hepatocyte necrosis at 4 weeks of age
|
|
• at 4 and 8 weeks
|
|
• in hepatocyte mitochondria at 2 weeks of age
• however, respiration activity has recovered by 4 and 8 weeks of age
|
|
• at 1 year, most mice develop hepatocellular carcinomas with tumor cells that are pleomorphic and often steatotic with frequent mitotic figures and variably anaplastic nuclei
|
|
• scattered lobular mixed inflammation with focal hepatocyte necrosis and prominent bile ductular proliferation at 4 weeks of age
• increasing portal/perioral and lobular mixed inflammation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice are smaller 1 month after birth
|
|
• livers are enlarged in 2-week old mice
|
|
• total plasma cholesterol levels are reduced in P35 and P90 mice fed normally or under fasting conditions
|
|
• total plasma triglyceride levels are reduced in P35 and P90 mice fed normally or under fasting conditions
• however, P35 and P90 mice exhibit normal albumin and glucose levels under fasting conditions
|
|
• total cholesterol levels in the liver are increased in P35 mice fed a normal chow diet or when fasted for 16 hours
• however liver total cholesterol levels are similar to controls in P90 fasted mice
|
|
• liver triglyceride levels are increased in in P35 mice fed a normal chow diet or when fasted for 16 hours and in P90 fasted mice
|
|
• 30% of livers develop nodular morphology with lipid storage disease-like structures in 1 year old mice
|
|
• livers are enlarged in 2-week old mice
|
|
• total cholesterol levels in the liver are increased in P35 mice fed a normal chow diet or when fasted for 16 hours
• however liver total cholesterol levels are similar to controls in P90 fasted mice
|
|
• liver triglyceride levels are increased in in P35 mice fed a normal chow diet or when fasted for 16 hours and in P90 fasted mice
|
|
• size and number of lipid droplets are increased in hepatocytes
• hepatocytes exhibit distended endoplasmic reticulum and particles with density similar to lipid droplets are seen in the lumen
• small particles with density similar to lipid droplets are not seen within the membrane-bound secretory vesicles of the Golgi apparatus as in wild-type hepatocytes
|
|
• fatty liver is seen as early as P1 and through adulthood
• size and number of lipid droplets are increased in hepatocytes
|
|
• livers are pale in 2-week old mice
|
|
• quantitative lipidomic and proteomic analyses indicate impaired secretion of different types of lipids and proteins, including VLDL, from the liver
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• induction of hepatic lipogenesis when fed Western diet
|
|
|
• both total and free when fed Western diet
|
|
|
• when fed Western diet
|
|
|
• when fed Western diet
|
|
|
• both total and free when fed Western diet
|
|
|
• when fed Western diet
|
|
|
• when fed Western diet
|
|
|
• both total and free when fed Western diet
|
|
|
• when fed Western diet
|
|
|
• when fed Western diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Livers of Cdk1tm2.1Kald/Cdk1tm2.1Kald Speer6-ps1Tg(Alb-cre)21Mgn/0 mice conatin fewer hepatocytes
|
• following partial hepatectomy, hepatocytes fail to enter cell division unlike control cells
• however, DNA replication is normal
|
|
• in untreated mice and following partial hepatectomy, hepatocytes exhibit increased nuclei diameter and decreased cell density compared with control cells
|
|
• in untreated mice and following partial hepatectomy
|
|
• in hepatocytes following partial hepatectomy
|
|
• following partial hepatectomy, hepatocytes fail to enter mitosis unlike control cells
|
|
• following partial hepatectomy, hepatocytes fail to enter cell division unlike control cells
• however, DNA replication is normal
|
|
• following tail-vein injection of activated Ras, mice fail to develop liver tumors unlike control mice
|
|
• following partial hepatectomy, hepatocytes fail to enter cell division unlike control cells
• however, liver regeneration is achieved through cell growth
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
N |
• when fed Western diet
• circulating triglyceride level
• liver triglyceride level
• circulating free fatty acid level
• liver free fatty acid level
• circulating cholesterol level both total and free
|
|
|
• both total and free when fed Western diet
|
|
|
• both total and free when fed Western diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increase in serum ALT levels, however ALT levels are lower than in single conditional Ptpn11 mice
|
|
• mutants exhibit an increase in hepatocellular carcinoma development after diethylnitrosamine (DEN) injection compared to controls and single conditional Ptpn11 mutants, however tumor frequency and size are similar to that seen in single conditional Stat3 mutants
|
|
• infiltrate of inflammatory cells is seen in the portal triads of livers
• double mutants show less inflammation than seen in single conditional Ptpn11 mice, with reduced size of eosinophilic vacuoles of degeneration in the liver
|
|
• infiltrate of inflammatory cells is seen in the portal triads of livers
• double mutants show less inflammation than seen in single conditional Ptpn11 mice, with reduced size of eosinophilic vacuoles of degeneration in the liver
|
|
• mutants exhibit an increase in hepatocellular carcinoma development after diethylnitrosamine (DEN) injection compared to controls and single conditional Ptpn11 mutants, however tumor frequency and size are similar to that seen in single conditional Stat3 mutants
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increased immature cholangiocyte-like and oval cells as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• increased immature cholangiocyte-like and oval cells as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• about 25-30% increase in fasting glucose levels at 1 month of age
|
|
• glucose intolerance
|
| N |
• the liver phenotype observed in single Pten mutants is significantly reduced, with liver weights, triglyceride levels in the liver and fatty liver almost similar to controls
|
|
|
• progenitor cell accumulation in the periductal region of livers occurs later than in single conditional Pten homozygotes, when injury conditions are already present
|
|
|
• mice do not show development of steatosis compared to single conditional Pten homozygotes
|
|
|
• mice exhibit a 6-month delay in liver tumor onset compared to conditional Pten homozygotes
• no mice develop liver tumors between 9 and 12 months of age and 25% of mice older than 12 months develop liver nodules
• however, treatment of 3 month old mice with 3,5-dietoxycarbonyl-1,4 dihydrocollidine (DDC) to induce liver injury leads to massive expansion of hepatic progenitors and development of premalignant lesions
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mean survival is 19 weeks of age
|
|
• mutants develop intrahepatic cholangiocarcinoma as early as 9 weeks of age
• intrahepatic cholangiocarcinoma is associated with intraductal papillary neoplasms of the bile ducts and Von Meyenburg complexes, or biliary hamartomas
• intrahepatic cholangiocarcinoma is characterized by elevated levels of autophagy
• different grades of differentiation are seen in the same tumor
|
|
• tumors are highly metastatic, with 75% of mutants having tumors showing invasion into adjacent organs such as the diaphragm, bowel, pancreas and stomach or distant metastasis to the lymph nodes, spleen, lungs, or peritoneal cavity
|
|
• intrahepatic cholangiocarcinoma is associated with biliary hamartomas
|
|
• hepatic lesions frequently show hemorrhage into the peritoneal cavity and exhibit evidence of tumor necrosis
|
|
• mutants develop intrahepatic cholangiocarcinoma as early as 9 weeks of age
• intrahepatic cholangiocarcinoma is associated with intraductal papillary neoplasms of the bile ducts and Von Meyenburg complexes, or biliary hamartomas
• intrahepatic cholangiocarcinoma is characterized by elevated levels of autophagy
• different grades of differentiation are seen in the same tumor
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| intrahepatic cholangiocarcinoma | DOID:4928 | J:184949 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• under fasting and refeeding conditions
|
|
• mice develop diabetes
• however, over-expression of a dominant negative Foxo1 by adenoviral transfection improves diabetes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mean survival is 52 weeks of age
|
|
• mutants develop intrahepatic cholangiocarcinoma as early as 32 weeks of age
• intrahepatic cholangiocarcinoma recapitulates the histologic and molecular features of multistage progression of human intrahepatic cholangiocarcinoma
• intrahepatic cholangiocarcinoma is associated with intraductal papillary neoplasms of the bile ducts and Von Meyenburg complexes, or biliary hamartomas
• intrahepatic cholangiocarcinoma is characterized by elevated levels of autophagy
• different grades of differentiation are seen in the same tumor
|
|
• tumors are highly metastatic, with tumors showing invasion into adjacent organs such as the diaphragm, bowel, pancreas and stomach or distant metastasis to the lymph nodes, spleen, lungs, or peritoneal cavity
|
|
• intrahepatic cholangiocarcinoma is associated with biliary hamartomas
|
|
• hepatic lesions frequently show hemorrhage into the peritoneal cavity and exhibit evidence of tumor necrosis
|
|
• mutants develop intrahepatic cholangiocarcinoma as early as 32 weeks of age
• intrahepatic cholangiocarcinoma recapitulates the histologic and molecular features of multistage progression of human intrahepatic cholangiocarcinoma
• intrahepatic cholangiocarcinoma is associated with intraductal papillary neoplasms of the bile ducts and Von Meyenburg complexes, or biliary hamartomas
• intrahepatic cholangiocarcinoma is characterized by elevated levels of autophagy
• different grades of differentiation are seen in the same tumor
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| intrahepatic cholangiocarcinoma | DOID:4928 | J:184949 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• median survival is 46 days
|
|
• seen in 5 month old mice
|
|
• all mice start to show abdominal distension at about 5 weeks of age, frequently accompanied by jaundice and weight loss
• distension is due to hepatic enlargement and/or hemorrhagic ascites
|
|
• tumors primarily show glandular morphology that resembles well-differentiated human cholangiocarcinoma and marker analysis indicates that tumors are intrahepatic cholangiocarcinoma
• in some cases, regions of moderately differentiated tumor with a cribriform appearance are seen
• no metastasis or invasion to other organs is seen
• tumors are frequently surrounded by dense fibrous stroma, indicating accumulation of fibrillar collagens
• stellate cells are activated and acquire a myofibroblast-like phenotype
• tumor cells show mucin production, a characteristic of epithelial cells in the bile duct
|
|
• multiple solid tumors with various sizes are seen throughout the liver
• invasive tumors are apparent after 7 weeks of age, with abundant desmoplastic stroma or desmoplasia
|
|
• various degrees of hyperplasia are seen in the bile ducts, characterized by increase in number and size and change in morphology, at 4 weeks of age
• at 5 weeks, a part of the hyperplastic ductal lesions at the hilum become enlarged and show a pattern of papillary growth
|
|
• various degrees of hyperplasia are seen in the bile ducts, characterized by increase in number and size and change in morphology, at 4 weeks of age
• at 5 weeks, a part of the hyperplastic ductal lesions at the hilum become enlarged and show a pattern of papillary growth
|
|
• tumors primarily show glandular morphology that resembles well-differentiated human cholangiocarcinoma and marker analysis indicates that tumors are intrahepatic cholangiocarcinoma
• in some cases, regions of moderately differentiated tumor with a cribriform appearance are seen
• no metastasis or invasion to other organs is seen
• tumors are frequently surrounded by dense fibrous stroma, indicating accumulation of fibrillar collagens
• stellate cells are activated and acquire a myofibroblast-like phenotype
• tumor cells show mucin production, a characteristic of epithelial cells in the bile duct
|
|
• multiple solid tumors with various sizes are seen throughout the liver
• invasive tumors are apparent after 7 weeks of age, with abundant desmoplastic stroma or desmoplasia
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| intrahepatic cholangiocarcinoma | DOID:4928 | J:254370 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• some lesions are diagnosed as intrahepatic cholangiocarcinoma by the appearance of adenocarcinoma showing tubular and/or papillary structures with a fibrous stroma; these tumor cells show loss of Pten expression
|
|
• mice develop liver tumors at 6 months of age, showing obvious symptoms after 7 months with abdominal distension due to multiple tumors at later stages
• mice develop liver tumors with both hepatocyte and cholangiocyte differentiation
|
|
• majority of large nodules are hepatocellular dysplasia, a precursor lesion of hepatocellular carcinoma
|
|
• some lesions are diagnosed as intrahepatic cholangiocarcinoma by the appearance of adenocarcinoma showing tubular and/or papillary structures with a fibrous stroma; these tumor cells show loss of Pten expression
|
|
• mice develop liver tumors at 6 months of age, showing obvious symptoms after 7 months with abdominal distension due to multiple tumors at later stages
• mice develop liver tumors with both hepatocyte and cholangiocyte differentiation
|
|
• majority of large nodules are hepatocellular dysplasia, a precursor lesion of hepatocellular carcinoma
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice fed a 0.03% cholic acid-supplemented diet directly from weaning die within a week after the start of the diet
• however, mice fed a 0.03% cholic acid-supplemented diet starting at 4 weeks of age for 4 weeks survive
|
|
• mice fail to gain weight and even lose weight after starting of 0.03% cholic acid-supplemented diet at 4 weeks of age
|
|
• liver weights are increased in mice fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age
• mice fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age do not exhibit fibrosis in the liver
|
|
• after 4 weeks of cholic acid-supplemented diet started at 4 weeks of age, mice exhibit enhanced plasma bilirubin levels
|
|
• after 4 weeks of cholic acid-supplemented diet started at 4 weeks of age, mice exhibit a mild elevation in plasma alanine transaminase levels
|
|
• after 4 weeks of cholic acid-supplemented diet started at 4 weeks of age, mice exhibit a mild elevation in plasma alkaline phosphatase levels
|
|
• after 4 weeks on a cholic acid-supplemented diet, plasma bile salts predominantly consist of about 90% taurocholate (TC) and about 7% tauro-beta-muricholate (TbetaMC) and a low concentration of about 0.4% of the secondary bile salt taurochenodeoxycholate (TDC) is seen compared to about 70% TC and 20% TbetaMC in single Atp8b1 homozygotes
• after 4 weeks on a cholic acid-supplemented diet, biliary bile salts predominantly consist of about 90% TC and about 9% TbetaMC compared to 55% TC and 40% TbetaMC in single Atp8b1 homozygotes
• after 4 weeks on a cholic acid-supplemented diet, bile salt hydrophobicity index of plasma is elevated but the hydrophobicity index of bile is unaltered, indicating that the plasma bile salt pool is more hydrophobic
|
|
• after 4 weeks of cholic acid-supplemented diet started at 4 weeks of age, mice exhibit a strong elevation in plasma bile salt levels
|
|
• mice fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age, exhibit a slight increase in bile duct proliferation
|
|
• liver weights are increased in mice fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age
• mice fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age do not exhibit fibrosis in the liver
|
|
• after 4 weeks of cholic acid-supplemented diet started at 4 weeks of age, bile flow is strongly (about 3-fold) reduced
• mice, however show normal bile salt output when fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age
|
|
• mice fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age develop a severe cholestatic phenotype with mild liver damage
|
|
• mice fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age, exhibit a slight increase in bile duct proliferation
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| intrahepatic cholestasis | DOID:1852 | J:215915 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutants are more vulnerable to hepatectomy surgery and most are either moribund or die by 48 hours after surgery
|
|
• mutants develop hemorrhagic liver destruction within the first few hours in response to apoptotic stimuli induced by Fas (Tnfrsf6) antibody compared to only minor liver damage in controls
|
|
• primary hepatocytes show reduced phagocytic activity towards bacteria (E.coli) than control cells
|
|
• hepatocytes exhibit increased sensitivity to Fas (Tnfrsf6)-induced apoptosis
|
|
• the ability of mutant livers to clear necrotic tissue and to repopulate the injured (by CCl4 exposure) area by regenerating hepatocytes is impaired
• associated with a persistent inflammatory reaction, overproduction of osteopontin, early and prominent dystrophic calcification, and impaired hepatocyte scattering/migration into diseased areas
|
|
• 80% of mutants die of acute liver failure in response to apoptotic stimuli induced by Fas (Tnfrsf6) antibody while controls survive
|
|
• mutants develop hemorrhagic liver destruction within the first few hours in response to apoptotic stimuli induced by Fas (Tnfrsf6) antibody compared to only minor liver damage in controls
|
|
• mutants exhibit delayed healing after toxic liver injury induced by CCl4 exposure
|
|
• mutants are more vulnerable to hepatectomy surgery and most are either moribund or die by 48 hours after surgery
|
|
• hepatocytes fail to migrate in a standard wound healing assay
|
|
• hepatocytes exhibit increased sensitivity to Fas (Tnfrsf6)-induced apoptosis
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• liver is larger in 10 week old mice and further enlarged at 40 weeks
|
|
• liver weight per body weight ratio is increased 2-fold at 10 weeks and 3-fold at 40 weeks
|
|
• mild sinusoidal fibrogenic changes and accumulations of lobular inflammatory cells are seen by 40 weeks of age
|
|
• increase in hepatocyte proliferation at 10 weeks of age
• however, no differences in hepatocyte apoptosis are seen at 10 or 40 weeks of age
|
|
• liver is larger in 10 week old mice and further enlarged at 40 weeks
|
|
• liver weight per body weight ratio is increased 2-fold at 10 weeks and 3-fold at 40 weeks
|
|
• triglyceride levels are increased in the liver at 10 weeks of age and are highly elevated at 40 weeks of age
• however, no differences in liver levels of free fatty acids, free cholesterol, or phospholipids are seen
|
|
• hepatocytes acquire expression of an adipocyte-specific marker
|
|
• Mallory bodies are frequently seen in hepatocytes by 40 weeks of age
|
|
• absolute numbers of total liver cells are almost normal at 10 weeks of age but increased by 1.5-fold at 40 weeks
|
|
• cytoplasm of liver cells is weakly eosinophilic and contains numerous microvesicular vacuoles containing lipids at 10 weeks of age; vacuolar changes are seen mainly around the central vein
• steatotic changes are more prominent in male than female mice
• by 40 weeks of age, livers show fatty changes of increased severity throughout the hepatic lobule such that aged liver resembles adipocytes in fat tissues
• however, no fibrotic changes are seen in the liver
|
|
• livers are light-colored at 10 weeks of age and homogenously white in color at 40 weeks
|
|
• hepatocellular carcinomas are seen in 5 of 6 males and 3 of 6 females; the hepatocellular carcinomas develop within liver adenomas and contain many fewer cytoplasmic lipid droplets than the adenomas
|
|
• macroscopic hepatic tumors are present in 66% of male and 30% of female mice at 40-44 weeks of age; nodular lesions resemble liver adenomas and cells with large droplets in the cytoplasm are prominent in most adenomas
|
|
• cholesterol ester levels are increased in the liver at 10 weeks of age and are highly elevated at 40 weeks of age
|
|
• glucose levels are lower in fasted mutants both before and after oral glucose administration
|
|
• serum insulin levels are reduced at 12 weeks of age
|
|
• serum levels are elevated at 40 weeks of age but not at 10 weeks of age
|
|
• serum levels are elevated at 40 weeks of age but not at 10 weeks of age
|
|
• serum levels are elevated at 40 weeks of age but not at 10 weeks of age
|
|
• intraperitoneal insulin injection reduces glucose levels by a greater amount than in wild-type mice indicating insulin hypersensitivity
|
|
• 16-carbon monosaturated fatty acids (C16:1) and C18:1 fatty acids are increased in livers of 10 week old mice and C16:0, C16:1, C18:0, C18:1, and C18:2 fatty acids are increased in livers of 40 week old mice
|
|
• triglyceride levels are increased in the liver at 10 weeks of age and are highly elevated at 40 weeks of age
• however, no differences in liver levels of free fatty acids, free cholesterol, or phospholipids are seen
|
|
• hepatocellular carcinomas are seen in 5 of 6 males and 3 of 6 females; the hepatocellular carcinomas develop within liver adenomas and contain many fewer cytoplasmic lipid droplets than the adenomas
|
|
• macroscopic hepatic tumors are present in 66% of male and 30% of female mice at 40-44 weeks of age; nodular lesions resemble liver adenomas and cells with large droplets in the cytoplasm are prominent in most adenomas
|
|
• 2 mutants with hepatocellular carcinoma show lung metastasis
|
|
• mild sinusoidal fibrogenic changes and accumulations of lobular inflammatory cells are seen by 40 weeks of age
|
|
• increase in hepatocyte proliferation at 10 weeks of age
• however, no differences in hepatocyte apoptosis are seen at 10 or 40 weeks of age
|
|
• cholesterol ester levels are increased in the liver at 10 weeks of age and are highly elevated at 40 weeks of age
|
|
• hepatic hydrogen peroxide levels in the liver are increased 7-fold, indicating increased production of reactive oxygen species
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| hepatocellular carcinoma | DOID:684 |
OMIM:114550 |
J:90905 | |
| steatotic liver disease | DOID:9452 |
OMIM:228100 |
J:90905 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increased immature cholangiocyte-like and oval cells but far less than in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• much less than in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• much less than in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• increased immature cholangiocyte-like and oval cells but far less than in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• much less than in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• homozygous mice exhibit no discernable phenotype; mice are viable and fertile with normal liver metabolism and normal glucose homeostasis
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• area of atherosclerotic lesions is reduced by about 53% compared to mice homozygous null for Apoe alone
|
|
• cholesterol levels are approximately 30% lower in Western diet fed mice compared to diet matched controls
|
|
• expression analysis indicates bile acid metabolism is reduced
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• paternal allele specific methylation is maintained
• maternal Igf2 allele expression is detected in the neonate liver
• paternal Igf2 allele expression is reduced
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• unlike most wild-type mice, mutant mice survive following intraperitoneal administration of 600-mg or 700-mg acetaminophen/kg body weight
|
|
• unlike most wild-type mice, mutant mice survive following intraperitoneal administration of 600-mg or 700-mg acetaminophen/kg body weight
|
|
• much milder hepatic injury in livers of mutant mice following acetaminophen exposure
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal hepatic triglyceride content, serum aspartate aminotransferase and alanine aminotransferase indicating a lack of hepatic injury
|
|
• mice exhibit higher serum insulin levels 4 and 6 hours after the start of refeeding unlike wild-type mice
|
|
• mice exhibit insulin resistance under refeeding conditions
• however, mice do not exhibit insulin resistance under fasting conditions
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at 10 weeks of age
|
|
• by 40 weeks of age, livers contain Mallory bodies, ballooning hepatocytes and accumulation of lobular inflammatory cells
|
|
• beginning at 10 weeks of age, mice exhibit enlargement of the liver that progressed further by 40 weeks of age
|
|
• at 10 and 40 weeks of age
|
|
• at 10 and 40 weeks of age
|
|
• at 10 weeks of age, the cytoplasm of hepatocytes contain lipid-filled micro- and macro-vesicular vacuoles unlike in wild-type mice
• at 40 weeks of age, micro- and macro-vesicular vacuoles coalesce to and displace the nucleus
|
|
• by 40 weeks of age, livers contain Mallory bodies
|
|
• at 10 weeks of age
|
|
• at 40 weeks of age
|
|
• beginning at 10 weeks of age, mice exhibit a pale liver that is white by 40 weeks of age
|
|
• at 74 to 78 weeks of age, 83% of males and 50% of females exhibit hepatocellular carcinomas that develop within liver adenomas and contain fewer lipid droplets than the adenomas
• 2 of 6 mice exhibit metastasis of hepatocellular carcinomas to the lungs
|
|
• at 40 weeks of age, 66% of males and 30% of females exhibit liver adenomas that contain large lipid droplets
|
|
• the polyploid mononuclear hepatocyte population is enriched in the liver of 3 and 10 month old mutants
• highly polyploid hepatocytes are also present in hepatocellular tumors in the livers
|
|
• at 10 weeks of age, hepatocyte proliferation is increased while apoptosis rates are normal
|
|
• at 74 to 78 weeks of age, 83% of males and 50% of females exhibit hepatocellular carcinomas that develop within liver adenomas and contain fewer lipid droplets than the adenomas
• 2 of 6 mice exhibit metastasis of hepatocellular carcinomas to the lungs
|
|
• at 40 weeks of age, 66% of males and 30% of females exhibit liver adenomas that contain large lipid droplets
|
|
• at 40 weeks of age
|
|
• at 40 weeks of age
|
|
• at 10 and 40 weeks of age
|
|
• at 10 and 40 weeks of age
|
|
• at 10 weeks of age
|
|
• at 10 weeks of age, hepatocyte proliferation is increased while apoptosis rates are normal
|
|
• beginning at 10 weeks of age, mice exhibit enlargement of the liver that progressed further by 40 weeks of age
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| hepatocellular carcinoma | DOID:684 |
OMIM:114550 |
J:138099 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• early (0 to 60 minutes) concentrations of a drug mixture, which contains midazolam, phenacetin, metaprodol, chlorzoxazone and tolbutamide, administered intravenously are higher than in wild-type mice
• at 2 hours, concentrations of the drug mixture administered intravenously was lower than in wild-type mice
• mice exhibit faster drug clearance and AUC (except in the case of midazolam) compared to wild-type mice
• the half-lives of phenacetin, tolbutamide, chlorzozane and midazolam are longer than in wild-type mice
• metabolite production following administration of drugs intravenously is shifted to the right compared to in wild-type mice
• when the drug mixture is given orally, AUC, Cmax are higher and clearance is slower than in wild-type mice for midazolam, phenacetin and metoprolol
• AUC and Cmax for tolbutamide given orally are lower than in wild-type mice
• when tolbutamide is administered orally or intravenously on its own, AUC and Cmax are increased and clearance is decreased compared to in wild-type mice
• mice exhibit a 4-fold increase in bioavailability of orally administered midazolam compared to in wild-type mice
• mice exhibit a 50% decrease in bioavailability of tolbutamide when delivered in a mixture and a 100% increase in bioavailability when administered on its own compared to in wild-type mice
|
| N |
• liver morphology is normal
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• normal body weight and organ weights
|
| N |
• normal adiposity
|
| N |
• normal plasma levels of metabolites
• normal golucose tolerance tests and insulin tolerance tests
|
|
• liver acyl-CoA levels are 35% lower than controls on a normal diet and 25% lower than controls on a high fat diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at 1 to 2 months
|
|
• after 30 weeks, mice lack bile ducts or bile duct-like structures unlike wild-type mice
|
|
• livers fail to form mature bile ducts unlike in wild-type mice
|
|
• at 1 to 2 months, the liver contains multiple areas of injured hepatocytes unlike in wild-type mice
|
|
• mice exhibit progressive liver fibrosis with early periportal fibrosis at 20 weeks unlike wild-type mice
• at 30 weeks, mice exhibit advanced fibrosis with cirrhosis unlike wild-type mice
|
|
• after 30 weeks, mice lack bile ducts or bile duct-like structures unlike wild-type mice
|
|
• livers fail to form mature bile ducts unlike in wild-type mice
|
|
• at 1 to 2 months
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• liver is as enlarge as in Nf2tm2Gth/Nf2tm2Gth Tg(Alb-cre)21Mgn mice
• bile over-proliferation observed in Nf2tm2Gth/Nf2tm2Gth Tg(Alb-cre)21Mgn mice is suppressed
|
| N |
• mice do not develop bile duct hamartomas or hepatocellular carcinoma unlike Nf2tm2Gth/Nf2tm2Gth Tg(Alb-cre)21Mgn mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice do not exhibit bile duct proliferation
|
|
• slightly
|
|
• slightly
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at E18.5, multiple tubular structures surround each portal vein unlike in wild-type mice
|
|
• mice exhibit widespread bile duct hamartomas that expand into the deep liver parenchyma unlike wild-type mice
|
|
• at 1 year of age
|
|
• mice exhibit widespread bile duct hamartomas that expand into the deep liver parenchyma unlike wild-type mice
|
|
• at 1 year of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutants exhibit an increase in hepatocellular carcinoma development (increase in tumor number and size) after diethylnitrosamine (DEN) injection compared to controls
|
|
• mutants exhibit an increase in hepatocellular carcinoma development (increase in tumor number and size) after diethylnitrosamine (DEN) injection compared to controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• when fed a high fat diet, mice exhibit normal insulin resistance
• mice fed a high fat diet exhibit normal hepatic lipid accumulation
|
|
• mice fed a high fat diet exhibit less of an increase in insulin levels compared with control mice
|
|
• when fed a low fat diet
• however, there is no significant difference when mice are fed a high fat diet
|
|
• mice fed a high fat diet resist glucose intolerance with enhanced glucose clearance compared with control mice
|
|
• marginally reduced when fed normal chow
|
| N |
• whether fed a low fat or high fat diet, mice exhibit normal weight
|
| N |
• mice fed a high fat diet exhibit normal hepatic lipid accumulation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following lipopolysaccharide stimulation
|
|
• following lipopolysaccharide stimulation
|
|
• following lipopolysaccharide stimulation
|
|
• following lipopolysaccharide stimulation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increased immature cholangiocyte-like and oval cells but not as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• not as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• not as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• increased immature cholangiocyte-like and oval cells but not as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• not as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increased immature cholangiocyte-like and oval cells but not as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• not as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• not as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• increased immature cholangiocyte-like and oval cells but not as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
• not as much as in Mob1atm1.1Asuz/Mob1atm1.1Asuz Mob1bGt(CC0690)Wtsi/Mob1bGt(CC0690)Wtsi Tg(Alb-cre)21Mgn mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• liver almost doubled in size
|
|
• 65% reduction in serum cholesterol level
|
|
• 50% reduction in serum triglyceride level
|
|
• 90% reduction in bile acid volume in the gall bladder
|
|
• abnormal metabolism of acetaminophen and pentobarbital
|
|
• liver almost doubled in size
|
|
• macrovesicular fatty changes
|
|
• microvesicular fatty changes
|
|
• reduced fertility when mated with other null animals
|
|
• reduced litter size when mated with other null animals
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• liver almost doubled in size
|
|
• 65% reduction in serum cholesterol
|
|
• 50% reduction in serum triglyceride level
|
|
• 90% reduction in bile acid volume in the gall bladder
|
|
• altered metabolism of pentobarbital and acetominophen
|
|
• liver almost doubled in size
|
|
• macrovesicular fatty changes
|
|
• microvesicular fatty changes
|
|
• reduced fertility when mated with other null animals
|
|
• reduced litter size when mated with other null animals
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice exhibit areas of ductopenia within some portal tracts unlike wild-type mice
|
|
• mild
|
|
• mice exhibit areas of ductopenia within some portal tracts unlike wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice fed a cholic acid-supplemented diet for 8 weeks exhibit bile duct proliferation
|
| N |
• mice fed a 0.03% cholic acid-supplemented diet directly from weaning exhibit normal growth
|
|
• mice fed a cholic acid-supplemented diet for 8 weeks exhibit an increased liver to body weight ratio
|
|
• mice fed a cholic acid-supplemented diet for 8 weeks exhibit increased hepatocyte proliferation
|
|
• plasma bilirubin levels are mildly increased at weaning and are further increased after 8 weeks of 0.03% cholic acid-supplemented diet
|
|
• plasma alanine transaminase levels are strongly elevated after 8 weeks of cholic acid-supplemented diet
|
|
• plasma alkaline phosphatase levels are strongly elevated after 8 weeks of cholic acid-supplemented diet
|
|
• on a cholic acid-supplemented diet, plasma bile salts predominantly consist of about 90% taurocholate (TC) and about 7% tauro-beta-muricholate (TbetaMC) compared to about 60% TC and 23% TbetaMC in single Abcb4 homozygotes
• on a cholic acid-supplemented diet, biliary bile salts predominantly consist of about 90% TC and about 2.5% of the secondary bile salt taurochenodeoxycholate (TDC) compared to 75% TC and 20% TbetaMC in single Abcb4 homozygotes
• on a cholic acid-supplemented diet, the biliary hydrophobicity index, but not the plasma hydrophobicity index, is elevated, indicating a more hydrophobic biliary bile salt pool
• however, mice fed a cholic acid-supplemented diet for 8 weeks exhibit normal bile flow and biliary bile salt output
|
|
• plasma bile salt levels are strongly elevated after 8 weeks of cholic acid-supplemented diet
|
|
• mice fed a cholic acid-supplemented diet for 8 weeks exhibit increased hepatocyte proliferation
|
|
• mice fed a cholic acid-supplemented diet for 8 weeks exhibit bile duct proliferation
|
|
• mice fed a cholic acid-supplemented diet for 8 weeks exhibit an increased liver to body weight ratio
|
|
• mice fed a regular diet exhibit portal fibrosis
• mice fed a cholic acid-supplemented diet for 8 weeks exhibit portal fibrosis that is more severe than in single Abcb4 homozygotes
|
|
• mice fed a cholic acid-supplemented diet for 8 weeks develop a severe cholestatic phenotype with severe liver damage
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| intrahepatic cholestasis | DOID:1852 | J:215915 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• more obvious over time
|
|
|
• pale, yellowish, hardened with rare small white nodules
• severe liver damage at 42 weeks
• however, hepatic mitochondrial cholesterol content is normal
|
|
|
• more obvious over time
|
|
|
• of total cholesterol at 16 weeks and more so at 42 weeks
• of free cholesterol and cholesterol ester in the liver at 42 weeks
|
|
|
• 2- to 14-fold at 12 weeks
|
|
|
• 8-fold at 16 weeks
• 52-fold at 42 weeks
|
|
|
• foamy hepatocytes more so at 42 weeks than 16 weeks, resulting from accumulation of many small vacuoles in a hepatocyte
|
|
|
• small and large vacuoles at 16 and 42 weeks
• progressive steatohepatitis
|
|
• macrovesicular steatosis primarily located in the zone 1 and panlobular region
|
|
• microvesicular steatosis predominantly around zones 3 and 2
|
|
|
• progressive
|
|
|
|
|
|
• increased hepatic oxidative stress at 42 weeks
• however, hepatic endoplasmic reticulum stress is normal
|
|
|
• progressive steatohepatitis
|
|
N |
• mice exhibit normal VLDL triglyceride and plasma lipids
• mice exhibit normal insulin sensitivity
|
|
|
• reduced fatty acid oxidation in the liver
|
|
|
• at 42 weeks
|
|
|
• a few fatty acid species of diacylglycerol are decreased in the liver
|
|
|
• of total cholesterol at 16 weeks and more so at 42 weeks
• of free cholesterol and cholesterol ester in the liver at 42 weeks
|
|
|
• 2- to 14-fold at 12 weeks
|
|
|
• decreased hepatic phospholipid at 42, but not 16, weeks
|
|
|
• 8-fold at 16 weeks
• 52-fold at 42 weeks
|
|
|
• reduced triglyceride hydrolase activity in the liver at 16 and 42 weeks
|
|
|
• progressive steatohepatitis
|
|
|
• reduced fatty acid oxidation in the liver
|
|
|
• increased hepatic oxidative stress at 42 weeks
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• blood glucose levels are reduced in homozygotes from 9.1 to 28.9% in both the fed and fasted states compared to gender and age matched wild-type mice
|
|
• serum insulin levels are reduced at 2 months and 1 year of age
|
|
• both glucose injection and glucose clamp assays indicate improved glucose tolerance
|
|
• glycogen levels are reduced in 1 year old mutants; however circulating glyconeogenic precursor levels are normal
|
|
• peripheral and hepatic insulin sensitivity are increased
|
|
• free fatty acid plasma levels are mildly reduced
|
|
• retention of triglycerides in the liver is increased and circulating levels are decreased
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increased autophagy of mitochondria
|
|
• elevated plasma cholesterol
|
|
• many biochemical pathways involved in energy production are upregulated
|
|
• increased autophagy of mitochondria
|
|
• impaired mitochondrial respiration
|
|
• significant decrease in complex I and complex II-dependent respiratory chain capacity in liver
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Hepatomegaly and tumor-like protrusions in the liver of Ei24tm1Hzha/Ei24tm1Hzha Speer6-ps1Tg(Alb-cre)21Mgn/0 mice
|
• impaired autophagic flux in the liver at 3 months
|
|
• by 10 months, livers exhibit multiple tumor-like protusions with no signs of malignancy
|
|
• by 3 months
|
|
• disorganized hepatic lobules
|
|
• swollen hepatocytes with swollen mitochondria
|
|
• swollen
|
|
• by 3 months
|
|
• swollen
|
|
• impaired autophagic flux in the liver at 3 months
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• fasting and postprandial
|
|
• by 5 weeks of age
|
|
• fasting and postprandial
|
|
• at 3 months of age, triglyceride secretion is decreased 60% compared to in wild-type mice
|
|
• mice develop diabetes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Increased apoptosis in liver of Adartm1Knk/Adartm1Knk Speer6-ps1Tg(Alb-cre)21Mgn/0 mice
| N |
• no observed hematopoietic defects
|
|
• increased levels of enzymes indicating hepatocellular damage
|
|
• increased apoptosis among hepatocytes
|
|
• disorganized liver architecture at 6 weeks of age
|
|
• increased apoptosis among hepatocytes
|
|
• body size about 50-70% of controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• hepatocytes exhibit decreased VLDL binding, uptake, and degradation compared with wild-type cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• total plasma cholesterol reduced 27%
|
|
• plasma levels are 70% of levels in controls
|
|
• plasma levels are 40% of levels in controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 5-times in response to Bortezomib treatment
|
|
• following tamoxifen treatment
• following partial hepatectomy
• in response to Bortezomib treatment
|
|
• liver cells exhibit less rough endoplasmic reticulum content compared with control liver cells
|
|
• mice exhibit a slight increase in hepatic lipid content compared with control mice
• mice subjected to liver stress (partial hepatectomy or treatment with tamoxifen or Bortezomib) exhibit increased accumulation of lipids in the liver compared with control mice
• however, phospholipid synthesis is normal
|
|
• mice exhibit a slight increase in hepatic lipid content compared with control mice
• mice subjected to liver stress (partial hepatectomy or treatment with tamoxifen or Bortezomib) exhibit increased accumulation of lipids in the liver compared with control mice
• however, phospholipid levels in the liver are normal
|
|
• following tamoxifen-treatment
|
|
• following tamoxifen treatment
• following partial hepatectomy
• in response to Bortezomib treatment
|
|
• following tamoxifen-treatment, secretion of apolipoproteins from liver cells is decreased compared to in control mice
|
|
• 5-times in response to Bortezomib treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• aged mutants become leaner by 10.7% for males and 14.9% for females, with a significant decrease of their body weights at 1 year of age
|
|
• lobular architecture of the liver is distorted by the development of hyperplastic hepatocyte plates
|
|
• serum levels of alanine aminotransferase are higher than in controls
|
|
• serum levels of aspartate aminotransferase are higher than in controls
|
|
• injection of a single dose of diethylnitrosamine (DEN) on P15 results in an increase in the number and size of (hepatocellular carcinoma) liver tumors in mutants compared to controls
|
|
• intraperitoneal LPS injection elicits a stronger liver damage response in mutants than in controls as indicated by higher serum alanine aminotransferase levels
• mutants show a 130% increase in spleen size 14 days after LPS challenge as compared to 98% increase in controls indicating increased systemic inflammatory response
• mutants show increased inflammatory cell infiltration into hepatic parenchyma after LPS challenge
• circulating IL-6 and TNFalpha levels are increased following LPS injection
• LPS stimulation of isolated hepatocytes results in increased IL-6 secretion by mutant hepatocytes compared to controls
|
|
• 93% of mutant livers contain areas with infiltrate of inflammatory cells, concentrating around the portal triads with extension into the parenchyma
• necrotic zones of livers are always associated with inflammatory cells, whereas inflammation is occasionally observed without necrosis
• 8 of 19 aged mutants develop focal microgranuloma consisting of mononuclear inflammatory cells
|
|
• 93% of mutant livers contain areas with infiltrate of inflammatory cells, concentrating around the portal triads with extension into the parenchyma
• necrotic zones of livers are always associated with inflammatory cells, whereas inflammation is occasionally observed without necrosis
• 8 of 19 aged mutants develop focal microgranuloma consisting of mononuclear inflammatory cells
|
|
• one or several foci of pallor are noticeable on the liver surface of 34% of analyzed mutants
• beginning at 5 months of age, regenerative foci are noticeable in the liver and nodular regenerative hyperplasia is seen from 8 months of age
• hepatic inflammation and necrosis, leading to nodular regenerative hyperplasia
|
|
• liver shows small focal areas as well as large areas of parenchymal necrosis, with necrosis observed in 47% of mutants
|
|
• liver shows small focal areas of parenchymal necrosis
|
|
• lobular architecture of the liver is distorted by the development of hyperplastic hepatocyte plates
|
|
• hepatic parenchyma shows regenerative hyperplasia, with 13 of 19 livers having nodule formation
• the space between hepatocytes is reduced inside the nodules
|
|
• massive hepatocyte degeneration is seen inside of or surrounding the hyperplastic nodules, in association with vacuoles containing eosinophilic material, but not in the liver parenchyma
|
|
• fibrosis is seen at the portal triads but not near the necrosis or into the parenchyma
|
|
• from 12-18 months of age, one or a few hepatocellular adenomas are frequently seen in mutants; tumors bulge from the liver surface, are often paler than the hepatic parenchyma, but sometimes darker or red when accompanied by bleeding
• tumors are unencapsulated, well delimited and show expanding masses of hepatocytes
|
|
• injection of a single dose of diethylnitrosamine (DEN) on P15 results in an increase in the number and size of (hepatocellular carcinoma) liver tumors in mutants compared to controls
|
|
• from 12-18 months of age, one or a few hepatocellular adenomas are frequently seen in mutants; tumors bulge from the liver surface, are often paler than the hepatic parenchyma, but sometimes darker or red when accompanied by bleeding
• tumors are unencapsulated, well delimited and show expanding masses of hepatocytes
|
|
• liver shows small focal areas as well as large areas of parenchymal necrosis, with necrosis observed in 47% of mutants
|
|
• liver shows small focal areas of parenchymal necrosis
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| hepatocellular adenoma | DOID:0050868 | J:172422 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 30-40% lower than controls by 7 weeks of age
|
|
• low body weight recovers to near normal between 7 weeks and 3 months
|
|
• growth retardation starting about the third week after birth
|
|
• hepatomegaly at 10 weeks
|
|
• hypertrophic and hyperplastic hepatocytes particularly in pericentric region
|
| N |
• mice appear healthy and fertile with normal liver function through 14 months of age
|
|
• possible compression of liver sinusoids
|
|
• hepatomegaly at 10 weeks
|
|
• hypertrophic and hyperplastic hepatocytes particularly in pericentric region
|
|
• increased incidence after 12 months
|
|
• in the liver
|
|
• proliferation of smooth endoplasmic reticulum
|
|
• tubulation of inner membrane
|
|
• reduced numbers of curled and stacked cristae
|
|
• proliferation of pleomorphic mitochondria
• mitochondria are normal if catalase positive peroxisomes are present
|
|
• groups of lysoosomes as well as lipid drops observed
|
|
• impaired respiratory chain
|
|
• activity of mitchondrial complex II and IV are normal in the liver
• activity of mitochondrial complex I is less than 15% of normal in the liver at 20 weeks of age
• activity of citochondria complex III and V about 40% normal
• reduced membrane potential of liver mitochondria
• reduced ATP production
|
|
• beta oxidation in cultured hepatocytes is abnormal
|
|
• beta oxidation in cultured hepatocytes is abnormal
|
|
• whole blood pyruvate slightly decreased
|
|
• whole blood lactate is increased about 70%
|
|
• increased activity of the glycolytic pathway
|
|
• bile acid metabolism is considerably reduced
|
|
• increased incidence after 12 months
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• resistant to liver failure caused by intraperitoneal injection of anti-FAS antibody
• recruitment of tBID to liver mitochondria is reduced
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in 2 of 6 mice at 20 months
|
|
• in 2 of 6 mice at 20 months
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal glucose metabolism
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Abnormal liver structure in Mir122tm1.2Kgh/Mir122tm1.2Kgh Speer6-ps1Tg(Alb-cre)21Mgn/0 mice
|
• increased
|
|
|
• in tumor-bearing male mice
|
|
• increase in serum gamma-glutamyl transpeptidase
|
|
• in tumor-bearing mice
|
|
• 2-fold as early as 5 weeks of age
• in tumor-bearing mice
|
|
• 2.5-fold at 8 to 10 weeks of age
• at 6 months of age
|
|
• mice exhibit a small increase in de novo triglyceride synthesis compared with control mice
|
|
• as early as 5 weeks of age
|
|
• as early as 5 weeks of age
|
|
• as early as 5 weeks of age
|
|
• in tumor-bearing mice
|
|
• 2.5-fold at 8 to 10 weeks of age
• at 6 months of age
|
|
• increased
|
|
• 2.5-fold at 8 to 10 weeks of age
• at 6 months of age
|
|
• 2.5-fold at 8 to 10 weeks of age
• at 6 months of age
|
|
|
• at 12 to 17 months, 13 of 26 male mice develop liver tumors
|
|
|
• in 2 of 20 mice at 12 to 17 months of age
|
|
• mice exhibit a small increase in de novo triglyceride synthesis and reduced triglyceride secretion in the liver compared with control mice
|
|
• steatohepatitis with bridging fibrosis
• recruitment of monocytes and neutrophils to the liver
|
|
• increased proliferation
|
|
|
• at 12 to 17 months, 13 of 26 male mice develop liver tumors
|
|
|
• in 2 of 20 mice at 12 to 17 months of age
|
|
• 3-fold in the liver at 10 months
|
|
• 3-fold in the liver at 10 months
|
|
|
• in tumor-bearing male mice
|
|
|
• from monocytes and neutrophils in the liver
|
|
• from monocytes and neutrophils in the liver
|
|
• steatohepatitis with bridging fibrosis
• recruitment of monocytes and neutrophils to the liver
|
|
• 3-fold in the liver at 10 months
|
|
• 3-fold in the liver at 10 months
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• unlike in Irs1 and Irs2 double null mice, fasting glucose, insulin, and adiponectin levels, insulin resistance, fed glucose levels, hepatic glycogen levels, and glucose tolerance are normal
|
|
• mice exhibit a partial recovery of plasma HDL cholesterol levels compared to in Irs1 and Irs2 double knockout mice
|
|
• triglyceride secretion is decreased compared to in wild-type mice but increased compared to in Irs1 and Irs2 double knockout mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• doxycycline (Dox)-treated mice show a gradual reduction in the volume of adipose tissue
• when mice are taken off the Dox-containing diet, the fat tissue volume increases
|
|
• increase in serum free fatty acids in the fed state after 72 hours of induction with Dox
• however, Dox-treated mice maintain the same rate of fatty acid and cholesterol synthesis as controls in a biochemical assay for de novo lipid synthesis
|
|
• mice fed a doxycycline (Dox)-containing diet show a higher respiratory exchange ratio than wild-type mice during the dark phase
|
|
• mice exhibit a reduction in hepatic glucose release when exposed to Dox for 48 hours
• metabolic cage studies indicate higher glucose utilization in Dox-treated mice
|
|
• a 6-hour fast causes severe hypoglycemia within 48 hours after induction with Dox
|
|
• serum glucose levels start to decrease by 72 hours after induction with Dox under fed conditions
• administration of a PPAR-alpha agonist exacerbates the hypoglycemia in Dox-treated mice
|
|
• fed insulin levels start to decrease upon induction with Dox and are significantly lower by 72 hours of induction
• 96 hours after Dox-induction, fasted insulin levels are lower
|
|
• hepatic glycogen is severely depleted after 48 hours of induction with Dox
|
|
• livers of Dox-treated mice show a faster response to insulin exposure and isolated hepatocytes induced with Dox show an enhanced insulin response indicating hepatic insulin sensitivity
|
|
• hepatic triglyceride content is increased in Dox-treated mice
• a 6-hour fast increases liver triglyceride content acutely within 24 hours of Dox exposure
|
|
• the fasting effects of adipocyte lipolysis on hepatic triglyceride content are exacerbated in Dox-treated mice compared to wild-type mice
|
|
• liver mass is increased 1.7-fold within 48 hours of induction with Dox
• Dox-treated mice show reduced dry mass content per wet liver
• increase in total liver protein in Dox-treated mice
|
|
• hepatic glycogen is severely depleted after 48 hours of induction with Dox
|
|
• hepatic triglyceride content is increased in Dox-treated mice
• a 6-hour fast increases liver triglyceride content acutely within 24 hours of Dox exposure
|
|
• Dox-treated mice show an increase in hepatic lipid levels
• when mice are taken off the Dox-containing diet, the liver steatosis decreases rapidly
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• fasting and fed insulin concentrations are elevated
|
|
• severe glucose intolerance
|
|
• significant insulin resistance
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• fasting insulin concentration are elevated
|
|
• significantly glucose intolerant
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• normal fasting circulating insulin, triglyceride and non-esterified fatty acid levels
• normal food intake
• normal skeletal muscle glycogen deposition after fasting
• normal liver triglyceride levels after fasting
|
|
• transient reduction in fasting glucose levels
• normal after extended fasting
• normal after refeeding
|
|
• lower hepatic glycogen deposition after fasting
• rapid normalization of glycogen levels when given access to food after fasting
|
|
• reduction in circulating glucose after intraperitoneal injection of insulin
|
| N |
• normal liver size
|
|
• lower hepatic glycogen deposition after fasting
• rapid normalization of glycogen levels when given access to food after fasting
|
| N |
• normal body weight and liver size
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• hepatocellular swelling without lipidosis, characterized by abundant, lightly granular, pale, eosinophilic cytoplasm, is observed in some animals
|
|
• individual hepatocyte necrosis or apoptosis, and a few scattered foci of necrosis are seen, sometimes with secondary neutrophilic infiltrates, in some livers
|
|
• liver weight/body weight ratio is significantly increased in males and females, with no significant change in body weight observed
|
|
• liver is lighter red in color compared to normal liver
|
|
• at 3 weeks of age, plasma total cholesterol is decreased 30% compared to controls and is decreased 80% at 2 months of age
|
|
• liver microsomal NADPH-cytochrome P450 activity toward cytochrome c, NKK, and acetominophen (AP), as well heme oxygenase (HO) activity are decreased in mice at 3 weeks
• at 2 months of age, mice have 5-8% of normal activity levels toward NKK and AP, and barely detectable HO activity
|
|
• mice are still unconscious 10 h after a single 60 mg/kg dose of pentobarbital, unlike controls which regained righting reflex after about 30 min
|
|
• liver weight/body weight ratio is significantly increased in males and females, with no significant change in body weight observed
|
|
• individual hepatocyte necrosis or apoptosis, and a few scattered foci of necrosis are seen, sometimes with secondary neutrophilic infiltrates, in some livers
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at 2 months of age, mice have ~25% of normal activity levels toward NKK and AP, and HO activity is below 5% compared to controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal glucose homeostasis under fed, fasted and re-fed conditions
|
|
• in unchallenged mice
|
|
• in unchallenged and fasted mice
|
|
• in unchallenged mice
|
|
• in fasted mice
|
|
• in fasted mice
|
|
• in fasted mice
|
|
• in fasted mice
|
|
• following a 24 h fast, hepatocytes surrounding the portal veins are more eosinophilic with vacuolization than in perivenous hepatocytes unlike in control mice
• re-fed mice exhibit rapid and variable development of giant vacuoles (dilated rough endoplasmic reticulum) in periportal hepatocytes unlike in control mice
• orally administration of casein to fasted mice exhibit vacuolization of periportal hepatocytes unlike in control mice
• administration of amino acids to fasted mice exhibit varying degrees of hepatocyte vacuolization depending on the amino acid (glutamine, glutamate, glycine>alanine>arginine>lysine) unlike in control mice
• fasted mice treated with ammonium acetate or pyruvate exhibit some degree of vacuolization unlike control mice
• however, oral administration of glucose, urea or triglyceride to fasted mice does not induce vacuolization
|
|
• dilated in the hepatocytes of mice that were fasted and re-fed
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• by P7 few bile ducts are present
|
| N |
• blood urea nitrogen levels are normal
|
|
• in some mice
|
|
• in some mice
|
|
• in some mice
|
|
• at P8 to P9, mice are 19% lighter than wild-type
• at 4 to 5 weeks of age, mice are 15% lighter than wild-type
|
|
• by P7 few bile ducts are present
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• by P7 few bile ducts are present
|
| N |
• blood urea nitrogen levels are normal
|
|
• in some mice
|
|
• in some mice
|
|
• in some mice
|
|
• at P8 to P9, mice are 19% lighter than wild-type
• at 4 to 5 weeks of age, mice are 15% lighter than wild-type
|
|
• by P7 few bile ducts are present
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice appear grossly normal at E17.5 and adult mice are viable
|
| N |
• clot-containing blood vessels are well-organized and normal in appearance with intact structure
|
|
• focal fibrin deposits detected in blood vessels at E15.5 to E17.5 with vascular occlusion or hemorrhage
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• dramatically increased by 8 weeks of age
|
|
• expression analysis indicates more cells have re-entered the cell cycle and at 8 weeks of age the number of Ki67 positive hepatocytes is further increased
|
|
• liver architecture is distorted with the pericentral expression pattern of glutamine synthetase absent
|
|
• increased size with some being extremely enlarged and containing more than 3 nuclei indicating incomplete mitoses
|
|
• dramatically increased by 8 weeks of age
|
|
• expression analysis indicates more cells have re-entered the cell cycle and at 8 weeks of age the number of Ki67 positive hepatocytes is further increased
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• male mice exhibit a slight decrease in plasma T4 levels compared to in Ncor1tm1Anh control mice
|
|
• PTU treated mice exhibit decreased serum LDL cholesterol levels compared to in similarly treated Ncor1tm1Anh control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Vascular tumors in Vhltm1.1Jae/Vhl+ livers and vascular lesions in Vhltm1Jae/Vhltm1Jae Speer6-ps1Tg(Alb-cre)21Mgn/0 mice
|
• die between 6 and 13 weeks of age
|
|
• body weight is about 50% of wild-type
|
|
• severe
|
|
• numerous blood filled vascular cavities, but no large cavernous hemangiomas, are seen
|
|
• severe
|
|
• accumulation of neutral fats in hepatocytes is detectable by 2 weeks of age
(J:67505)
• severe steatosis
(J:97652)
|
|
• foci of increased vascularization are present in the liver
|
|
• proliferation of endothelial cells in hepatic blood vessels
|
|
• hepatic vascular angiectasia
|
|
• hepatic vascular angiectasia
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| von Hippel-Lindau disease | DOID:14175 |
OMIM:193300 |
J:67505 , J:97652 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at 2 months of age, mice show hyperglycemia in the fed state
• however, blood glucose levels become normal by 6 months of age
|
|
• at 2 months of age, mice show hyperinsulinemia in the fed state that is more severe than in Mad2l1bptm1.1Itl/Mad2l1bptm1.1Itl Speer6-ps1Tg(Alb-cre)21Mgn/Speer6-ps1+ mice
|
|
• at 2 months of age, mice show severe glucose intolerance
• surprisingly, glucose intolerance is not severe at 6 months of age
|
|
• at 2 months of age, liver glycogen levels are decreased to a greater extent than in Mad2l1bptm1.1Itl/Mad2l1bptm1.1Itl Speer6-ps1Tg(Alb-cre)21Mgn/Speer6-ps1+ mice
|
|
• at 2 months of age, mice show severe insulin intolerance
• surprisingly, insulin intolerance is not severe at 6 months of age
|
|
• insulin treatment fails to stimulate glycogen synthase activity in hepatocytes, unlike in wild-type hepatocytes
|
|
• at 2 months of age, males show scattered focal dysplasia in the periportal area of the liver
• however, overall liver architecture is normal
|
|
• at 2 months of age, liver glycogen levels are decreased to a greater extent than in Mad2l1bptm1.1Itl/Mad2l1bptm1.1Itl Speer6-ps1Tg(Alb-cre)21Mgn/Speer6-ps1+ mice
|
|
• insulin receptor (IR) autophosphorylation and activating phosphorylation of AKT (pT308) are significantly reduced whereas inhibitory phosphorylation of GSK3 (pS9) is modestly reduced in whole-liver lysates from insulin-treated mice
|
|
• insulin-dependent glycogen synthase (GS) activation is abolished in hepatocytes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at 3 months
|
|
• decreased fatty acid oxidation in the liver
|
|
• after 48 hours of fasting
|
|
• without a change in macrophage numbers, fibrosis or apoptosis
|
|
• at 3 months
|
|
• heat production after 48 hours of fasting is lower than in wild-type mice
|
|
• cholangiocytes contain lipid droplets unlike in wild-type mice
|
|
• at 3 months
|
|
• at 3 months
|
|
• increase in size and number of hepatocyte lipid droplets
• increased lipolysosomes
|
|
• progressive macrovesicular steatosis
|
|
• pericentral microvesicular steatosis
|
|
• decreased fatty acid oxidation in the liver
|
|
• cholangiocytes contain lipid droplets unlike in wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• all mice develop cholangiocarcinoma-like lesions composed of dysplastic dust-like structures surrounded by fibrosis within 2 months of birth
|
|
• all mice develop cholangiocarcinoma-like lesions composed of dysplastic dust-like structures surrounded by fibrosis within 2 months of birth
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• bile duct hyperplasia is seen in some mice at 8 months of age
|
|
• bile duct dilation is seen in some mice at 8 months of age
|
|
• bile duct hyperplasia is seen in some mice at 8 months of age
|
|
• bile duct dilation is seen in some mice at 8 months of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die at 6 to 8 weeks of age
|
|
• at 6 weeks, the liver is friable and stippled with irregular yellow spots on a reddish black background unlike in wild-type mice
• hepatic vascularity is increased compared to in wild-type mice
|
|
• at 6 weeks of age
|
|
• livers contain irregular, dilated, blood filled sinusoids and cytoplasmic vacuolizations within hepatocytes with eccentric nuclei unlike in wild-type mice
|
|
• in a mixed micro- and macrovesicular steatotic pattern
|
|
• hepatic vascularity is increased compared to in wild-type mice
|
|
• mice are runted
|
|
• at 6 weeks of age
|
|
• of paws and unfurred skin by 4 to 6 weeks of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutants develop invasive intrahepatic cholangiocarcinoma with low penetrance (1 of 8 mutants) and long latency (at 36 weeks of age)
|
|
• mice develop liver tumors at 12 months of age and do not show obvious symptoms up to 18 months of age
• tumors resemble hepatocellular dysplasia
|
|
• mutants develop invasive intrahepatic cholangiocarcinoma with low penetrance (1 of 8 mutants) and long latency (at 36 weeks of age)
|
|
• mice develop liver tumors at 12 months of age and do not show obvious symptoms up to 18 months of age
• tumors resemble hepatocellular dysplasia
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| intrahepatic cholangiocarcinoma | DOID:4928 | J:184949 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal hepatic triglyceride content, serum aspartate aminotransferase and alanine aminotransferase indicating a lack of hepatic injury
|
|
• mice exhibit higher serum insulin levels 24 hours after fasting and 30 and 60 minutes after the start of refeeding unlike wild-type mice
|
|
• mice exhibit insulin resistance under fasting conditions
• however, mice do not exhibit insulin resistance under refeeding conditions
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• gene expression analysis indicates that fat utilization and glucose production are promoted in mutants
|
|
• plasma triglyceride levels are lower than in wild-type mice, however adiponectin and leptin levels are no different
• mutants do not show an increase in plasma triglyceride levels in response to the high-fat diet as is seen in wild-type mice
|
|
• mutants exhibit mild but significant glucose intolerance
|
|
• mutants exhibit a slight reduction in systemic insulin sensitivity
• insulin levels at 30 minutes following glucose administration are higher in mutants than controls, indicating insulin resistance
• however, fasting plasma glucose and insulin levels are normal
|
| N |
• mutants normally do not exhibit hepatic steatosis, however when fed a high-fat diet and treated with rapamycin, they develop steatosis and show increased levels of hepatic triglycerides
|
|
• mutants develop hepatomegaly
|
|
• increase in hepatocyte cell size
|
|
• hepatocytes are resistant to steatosis induced by a high-fat diet
|
|
• mutants develop hepatomegaly
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• progressive hepatocyte cell death as mice progress from steatosis to premalignancy, with massive hepatocyte death by 9 months of age
|
|
|
• at 12 months of age, livers show increased cell proliferation
|
|
|
• progressive and chronic liver injury that begins before proliferation of hepatic progenitors
• accumulation of hepatic progenitor cells in the periductal region of livers from 9-12 months of age
• liver shows multiple layers of progenitor cells surrounding a single layer of ductal cells which show high mitotic activity after 9 months of age
|
|
• mutants exhibit enlarged, whitish livers containing large fat vacuoles by 12 weeks of age
(J:171445)
• mutants treated with rapamycin show reduced hepatocyte cell size, thus reducing the liver:body weight ratio
(J:171445)
|
|
• increase in glycogen storage in the liver
|
|
• 3-fold increase in triglyceride content in the liver
(J:88441)
• however, normal levels of plasma triglycerides
(J:88441)
• 2-4-fold increase of triglyceride content in the liver of 1 and 3 month old mutants, respectively
(J:160759)
|
|
• progressive development of fatty liver
(J:88441)
|
|
|
|
(J:218587)
|
|
• mutants exhibit enlarged, whitish livers containing large fat vacuoles by 12 weeks of age
• mutants treated with rapamycin exhibit no differences in steatosis compared to vehicle-treated mutants
|
|
|
• tumors show compact trabecular growth patterns and pseudoglandular structures of hepatocellular carcinoma and tubular features of cholangiocyte carcinoma
|
|
|
• mice develop liver tumors starting at approximately 8-9 months of age
• 50% of mice develop tumors between 9 and 12 months of age and 100% develop tumors by 12 months of age
• tumors show mixed cell characteristics, with tumors composed of colangiocytes, hepatocytes, and bi-lineage cells
|
|
|
• tumors show compact trabecular growth patterns and pseudoglandular structures of hepatocellular carcinoma and tubular features of cholangiocyte carcinoma
|
|
• 50% reduction in total body fat content
|
|
• decrease in fasting glucose levels at 1 and 3 months of age, however at 6 months of age, when severe steatosis is seen, the fasting glucose level is similar to wild-type
|
|
• decrease in fasting plasma insulin levels at 3 and 6 months of age
|
|
• decrease in serum leptin levels at one month of age
• however eating behavior is normal
|
|
|
• serum alanine aminotransferase levels increase progressively, reaching 5-fold higher levels at 12 months of age
|
|
• increase in glucose clearance during an intraperitoneal glucose load
|
|
• increase in glycogen storage in the liver
|
|
• increase in insulin sensitivity in the liver
|
|
• hepatocyte fatty acid uptake by passive diffusion is increased by 20% compared to controls, however active transportation of fatty acid is not changed and thus total fatty acid uptake is not significantly altered
• rate of fatty acid synthesis is 2.5-fold higher in mutant livers than in controls
|
|
• 30% decrease in circulating free fatty acids
|
|
• 3-fold increase in triglyceride content in the liver
(J:88441)
• however, normal levels of plasma triglycerides
(J:88441)
• 2-4-fold increase of triglyceride content in the liver of 1 and 3 month old mutants, respectively
(J:160759)
|
|
• decrease in lipolysis rate
|
|
• mutants exhibit enlarged, whitish livers containing large fat vacuoles by 12 weeks of age
(J:171445)
• mutants treated with rapamycin show reduced hepatocyte cell size, thus reducing the liver:body weight ratio
(J:171445)
|
|
|
• progressive hepatocyte cell death as mice progress from steatosis to premalignancy, with massive hepatocyte death by 9 months of age
|
|
|
• at 12 months of age, livers show increased cell proliferation
|
|
|
• marker analysis indicates oxidative stress in the liver
|
|
|
• tumors show compact trabecular growth patterns and pseudoglandular structures of hepatocellular carcinoma and tubular features of cholangiocyte carcinoma
|
|
|
• mice develop liver tumors starting at approximately 8-9 months of age
• 50% of mice develop tumors between 9 and 12 months of age and 100% develop tumors by 12 months of age
• tumors show mixed cell characteristics, with tumors composed of colangiocytes, hepatocytes, and bi-lineage cells
|
|
|
• tumors show compact trabecular growth patterns and pseudoglandular structures of hepatocellular carcinoma and tubular features of cholangiocyte carcinoma
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| hepatocellular carcinoma | DOID:684 |
OMIM:114550 |
J:218587 | |
| steatotic liver disease | DOID:9452 |
OMIM:228100 |
J:216841 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal liver morphology and outcome after partial hepatectomy
|
|
• CCl4-treated mice exhibit prominent central-to-central bridging fibrosis and a 4-fold increase more fibrotic area of collagen deposition in hydroxyproline accumulation compared with control mice
• 3 weeks following bile duct ligation, mice exhibit a 3-fold increase in fibrotic area compared with wild-type mice
|
|
• CCl4-treated mice exhibit prominent central-to-central bridging fibrosis, a 4-fold increase more fibrotic area of collagen deposition, 3-fold increase in hydroxyproline accumulation and fewer senescence cells around the central vein compared with control mice
• 3 weeks following bile duct ligation, mice exhibit a 3-fold increase in fibrotic area and hydroxyproline content and fewer senescent cells compared with wild-type mice
• however, CCl4-treated mice exhibit normal level of liver damage (serum alanine aminotransferase, cell proliferation and cell apoptosis) and myofibroblast apoptosis
|
|
• fewer senescence cells surrounding the hepatic central veins in CCl4-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mild reduction in ad libitum blood glucose levels in young mice
|
|
• increased reduction in glycaemia following injection of insulin in an insulin tolerance test
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at 10 to 12 months of age
|
|
• while mice display normoglycemia during the first 3 weeks of life, at 4 weeks mice develop hypoglycemia that lasts until week 6
|
|
• at 2 weeks beta cell mass is increased 2-fold and at 6 weeks 4-fold compared to in wild-type mice due to increased mitosis of beta cells
• at 10 to 12 months of age, mice exhibit a 27-fold increase in beta cell mass due to an 8-fold increase in proliferating beta cells with a slight increase in apoptosis
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 82% of mice die by 6 weeks of age with some mice surviving a few weeks longer
|
|
• mice develop hypoglycemia at 2 weeks of age that rapidly worsens by 6 weeks of age
• mice exhibit high fasting glucose serum levels
|
|
• during terminal stages
|
| N |
• unlike mice null for Insr in beta cells mice, islet cell mass is not increased despite similar levels of elevated insulin levels
|
|
• mice develop severe diabetes and loss 30% of their body weight in terminal stages
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice with liver-specific Ptpn1 deletion show similar body weight to Ptpn1-sufficient controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• these mutants fail to exhibit an adaptive islet hyperplastic response to insulin resistance; instead, pancreatic beta cell mass is reduced, and islets appear small with scattered non-beta cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• seen in older males
|
|
• tumor formation is more prevalent and starts earlier in males compared to females
|
|
• preneoplastic nodules are first detected at about 160 days of age in males
• liver nodules in quadruple transgenic mice are larger and more numerous compared to triple transgenic mice that are wild-type at the Trp53 locus
|
|
• seen in older males
|
|
• tumor formation is more prevalent and starts earlier in males compared to females
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• reduced aspartate transaminase activity
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at 6 months, mutant mice show a 50% increase in alkaline phosphatase levels, suggesting biliary tract dysfunction
|
|
• at 6 months, mutant mice show a 2.6-fold increase in aspartate aminotransferase levels, suggesting hepatocellular damage
• in contrast, no significant changes in levels of lactate dehydrogenase or alanine aminotransferase are observed
|
|
• at 6 months, mutant mice display a 50% reduction in serum albumin levels
|
|
• at 2 months, male mutants fail to suppress hepatic glucose output in response to insulin administration, despite intact insulin signaling in adipose tissue and nearly normal insulin signaling in muscle
|
|
• at 6 months, female mutants show a have 5- to 6-fold increase in pancreatic insulin content measured in acid-ethanol extracts
|
|
• at 2 months, male mutants exhibit significantly elevated blood glucose in the fed state, despite a 20-fold increase in insulin levels relative to control mice; in contrast, glucagon levels remain unaffected
• at 2 months, male mutants also display a mild hyperglycemia in the fasted state, despite a 7-fold increase in serum insulin levels
• unexpectedly, as mutant mice age, the elevated fasting blood glucose levels progressively decline; by 6 months of age, mutants exhibit fasting hypoglycemia rather than hyperglycemia
|
|
• at 2 months, male mutants exhibit an extreme increase in serum insulin levels (20-fold in fed state; 7-fold in fasted state)
|
|
• at 2 months, fasted male mutants display pronounced glucose intolerance
• surprisingly, glucose intolerance is no longer apparent at 6 months
|
|
• in addition to increased insulin secretion, 11-week-old male mutants show a 75% reduction in the C-peptide:insulin ratio, indicating decreased insulin clearance
|
|
• at 2 months, random-fed male mutants are severely resistant to the blood glucose-lowering effects of exogenously administered insulin
|
|
• at 2 months, male mutants show a 40-50% reduction in the levels of serum free fatty acids
|
|
• at 2 months, male mutants show a 40-50% reduction in the levels of serum triglycerides
|
|
• mutant gallbladders show a notable increase in bile volume
|
|
• at 6- to 12-months of age, mutant gall bladders appear enlarged
|
|
• at 2 months, mutant livers appear a little darker in color, with areas of focal dysplasia and reduced glycogen storage in the parenchyma; no steatosis is observed
• at 6- to 12-months of age, mutant livers display multiple hyperplastic pale nodules scattered throughout all lobes
• by 12 months, the normal lobular structure is disrupted; hyperplastic nodules consist of highly vacuolated cells that compress the adjacent normal tissue, in the absence of fibrosis
|
|
• at 6 months, mutant hepatocytes exhibit a moderate increase in lipid accumulation; only a few electron-dense glycogen granules are observed
|
|
• at 2 months, mutant livers are 40% smaller than those of age- and gender-matched controls; liver size decreases significantly with increasing age
|
|
• insulin resistance in liver results in elevated expression of PEPCK, the rate-limiting enzyme for gluconeogenesis, and reduced expression of glucokinase and liver pyruvate kinase, two enzymes critical for glucose utilization
• the mutant liver appears to be chronically geared toward glucose production; early insulin signaling events, such as IRS-1 and IRS-2 phosphorylation, are lost
|
|
• at 6 months, increased pancreatic insulin content is associated with a 6-fold increase in pancreatic beta cell mass
(J:63878)
• at 6 months, mutant mice show a ~4-fold increase in pancreatic beta cell mass, as a compensatory response to insulin resistance
(J:92861)
|
|
• at 6 months, mutant mice show an adaptive islet hyperplastic response to insulin resistance
|
|
• at 6- to 12-months of age, mutant gall bladders appear enlarged
|
|
• at 6 months, female mutants show a have 5- to 6-fold increase in pancreatic insulin content measured in acid-ethanol extracts
|
|
• at 6 months, mutant hepatocytes exhibit giant mitochondria
|
|
• at 6- to 12-months of age, mutant gall bladders appear enlarged
|
|
• newborn mutant mice appear normal, nurse successfully, and survive well upon weaning but display a mild growth deficit postweaning
• this moderate growth deficit appears to result from defects in the growth hormone-IGF axis (unpublished data)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal liver appearance and size
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• viability is normal
|
| N |
• iron and heme metabolism is normal unless fed delta aminolevulinic acid
|
|
• increased protoporphyrin IX in liver, plasma, and red blood cells when fed delta aminolevulinic acid
|
|
• when fed delta aminolevulinic acid
|
|
• increased collagen deposition when fed delta aminolevulinic acid, also occurs to a to lesser extent in heterozygotes
|
|
• bile accumulation occurs when fed delta aminolevulinic acid
|
|
• slightly enlarged when fed delta aminolevulinic acid
|
|
• slightly enlarged when fed delta aminolevulinic acid
|
|
• when fed delta aminolevulinic acid
|
|
• slightly enlarged when fed delta aminolevulinic acid
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Decreased bone density in Ghrtm1.1Masp/Ghrtm1.1Masp Speer6-ps1Tg(Alb-cre)21Mgn/0 mice
|
• 2 to 3 times
|
|
• 4-fold
|
|
• triglyceride secretion from the liver is impaired compared to in wild-type mice
|
|
• triglyceride secretion from the liver is impaired compared to in wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice survive to adulthood
|
| N |
• mice exhibit normal liver histology
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• hepatic glycogen content was decreased at birth, reduced in older mutant animals and was depleted after a 24 hour fast
|
|
• hepatic triglyceride levels were increased by 94% after a 24 hour fast
|
|
• after a 24 hour fast, the liver mass was increased by 71% over controls
|
|
• liver weight was increased by 18%
|
|
• hepatic glycogen content was decreased at birth, reduced in older mutant animals and was depleted after a 24 hour fast
|
|
• hepatic triglyceride levels were increased by 94% after a 24 hour fast
|
|
• after a 24 hour fast, the liver mass was increased by 71% over controls
|
|
• liver weight was increased by 18%
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• decreased (70-90%) phospholipid levels
|
|
• slightly higher catabolism of HDL apoA-I from wildtype mice or human lipid-free ApoA-I than in wildtype, due to an increase in the catabolism of apoA-I by the kidney, with no change in liver catabolism
|
|
• decreased levels of total plasma cholesterol, free cholesterol, and esterified cholesterol
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 70-90% reduction in plasma phospholipid level
|
|
• 2-fold higher catabolism of HDL apoA-I from wildtype mice or human lipid-free ApoA-I than in wildtype, due to a 2-fold increase in the catabolism of apoA-I by the kidney, with no change in liver catabolism
|
|
• total plasma cholesterol levels were 80% lower than in wildtype
• 70-90% reduction in plasma free cholesterol and esterified cholesterol
|
|
• 80% lower than in wildtype
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Tangier disease | DOID:1388 |
OMIM:205400 |
J:98093 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit a normal life span
|
|
• hepatocytes exhibit fine vacuolization unlike in wild-type mice but are otherwise normal
|
|
• moderate and in a microvesicular pattern
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die at 6 to 8 weeks of age
|
|
• at 6 weeks, the liver is friable and stippled with irregular yellow spots on a reddish black background unlike in wild-type mice
• livers exhibit vascular lesions observed in Vhltm1Jae/Vhltm1Jae Tg(Alb-cre)21Mgn mice with minimal evidence of vacuolization
• hepatic vascularity is increased compared to in wild-type mice
|
|
• at 6 weeks of age
|
|
• minimal
|
|
• hepatic vascularity is increased compared to in wild-type mice
|
| N |
• unlike in Vhltm1Jae/Vhltm1Jae Tg(Alb-cre)21Mgn mice, body weight is normal
|
|
• at 6 weeks of age
|
|
• of paws and unfurred skin by 4 to 6 weeks of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die at 6 to 8 weeks of age
|
|
• at 6 weeks, the liver is friable and stippled with irregular yellow spots on a reddish black background unlike in wild-type mice
• hepatic vascularity is increased compared to in wild-type mice
|
|
• at 6 weeks of age
|
|
• in a mixed micro- and macrovesicular steatotic pattern
|
|
• hepatic vascularity is increased compared to in wild-type mice
|
| N |
• unlike in Vhltm1Jae/Vhltm1Jae Tg(Alb-cre)21Mgn mice, body weight is normal
|
|
• at 6 weeks of age
|
|
• of paws and unfurred skin by 4 to 6 weeks of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• significantly increased serum ferritin levels at 10 weeks of age
|
|
|
• significantly elevated transferrin saturation at 10 weeks of age
|
|
|
• 13.1-fold decrease in hepcidin mRNA expression in liver
• 2.4-fold increase in hepatic BMP6 mRNA levels
• marked up-regulation of ferroportin in the duodenum
• however, duodenal BMP6 mRNA expression is largely normal
|
|
|
• 2.4-fold reduction of nonheme iron levels in spleen at 10 weeks of age
• splenic macrophages are iron-deficient
|
|
|
• significantly increased serum iron levels at 10 weeks of age
|
|
|
• 12.9-fold increase of nonheme iron levels in liver at 10 weeks of age, as determined by ferrozine assay
|
|
|
• deposits of nonheme iron in parenchymal cells of the liver, pancreas, and heart at 10 weeks of age
|
|
|
• splenic macrophages are iron-deficient
|
|
|
• 2.4-fold reduction of nonheme iron levels in spleen at 10 weeks of age
• splenic macrophages are iron-deficient
|
|
|
• 12.9-fold increase of nonheme iron levels in liver at 10 weeks of age, as determined by ferrozine assay
|
|
|
• splenic macrophages are iron-deficient
|
|
|
• 2.4-fold reduction of nonheme iron levels in spleen at 10 weeks of age
• splenic macrophages are iron-deficient
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• mutant males exhibit a significantly lower body weight than control males up to 3.5 months of age
• however, this difference is not visible after 4 months of age
|
|
|
• after 24 or 48 hr starvation, 4-month-old males display a greater % of body weight loss than control mice
|
|
|
• despite a higher EE, mutant mice gain more weight on a HFD and show increased fat mass and liver and perigonadal WAT weight gains than control mice
|
|
|
• mutant mice display enlarged livers
• after 16 weeks on a high-fat diet (HFD; 60% calories from fat), mutant mice exhibit significantly larger livers than control mice
|
|
|
• mutant mice exhibit an increased liver weight relative to body weight
|
|
|
• time for recovery of the righting reflex after zoxazolamine-induced paralysis is significantly increased relative to controls, indicating decreased liver function
|
|
|
• on a regular chow diet, mutant mice exhibit reduced physical activity relative to control mice
|
|
|
• mice are unable to internalize and degrade select proteins by chaperone-mediated autophagy (CMA)
• in vivo blockage of lysosomal proteolysis by i.p. injection of leupeptin revealed that GAPDH (a known CMA substrate) is no longer degraded in mutant liver lysosomes
• in contrast, lysosomal delivery and degradation of cytosolic proteins such as cyclophillin (a non-CMA substrate) is normal
|
|
|
• serum ALT levels are significantly increased, indicating hepatocyte damage
• after 16 weeks on a HFD, mice exhibit significantly greater serum ALT levels than control mice
|
|
|
• on a regular chow diet, mutant mice show significantly higher energy expenditure (EE) than control mice throughout a 24 hr cycle; however, no difference in food intake (meal number and size) is observed
• a HFD has a significantly smaller impact on lowering the EE in mutant mice relative to control mice
• after a 24 hr starvation, mutant mice exhibit a significantly higher EE than control mice during the day cycle
|
|
|
• fed mutant mice exhibit higher average values of CO2 production than control mice
|
|
|
• fed mutant mice exhibit higher average values of O2 consumption than control mice
|
|
|
• on a regular chow diet, mutant mice exhibit higher respiratory exchange ratio (RER) values than control mice during the 24 hr cycle
• mutant RER values remain higher than in controls during the first 6 hr of a 24 hr starvation period
|
|
|
• mutant livers exhibit higher lactate content and specific activity of glycolytic enzymes (GAPDH and PK), suggesting enhanced glycolysis
• in culture, primary hepatocytes from mutant mice show significantly higher basal glycolytic rates and maximal glycolytic capacity and higher levels of glycolytic enzymes relative to control hepatocytes; basal and maximal glycolytic capacity remains significantly higher than in controls even 24 hr after removal of serum from the culture media
• after a 24 hr starvation, levels of different glycolytic enzymes in mutant livers remain higher than in control livers
|
|
|
• after a 8 hr starvation (overnight fasting), mutant mice show a significant drop in blood glucose levels relative to control mice
• reduced blood glucose levels in response to short- and long-term fasting are noted even when mutant mice are fed a HFD
• lower blood glucose observed during starvation are not due to increased circulating insulin levels
|
|
|
• mutant mice display improved glucose tolerance even when placed on a HFD
• lower blood glucose observed during the glucose tolerance test are not due to increased circulating insulin levels
|
|
|
• biochemical analysis and PAS staining revealed a significant reduction of glycogen content in mutant livers
|
|
|
• following injection of a pyruvate bolus (converted into glucose in liver), overnight fasted mutant mice show a significantly smaller increase in blood glucose than controls, suggesting reduced hepatic gluconeogenesis
|
|
|
• mutant mice show a significant reduction in starvation-induced lysosomal degradation of liver enzymes related to lipid metabolism
• lysosomal degradation of some enzymes is also reduced even under fed conditions; accordingly, levels of many lipid metabolic enzymes are increased in mutant liver cytosolic fractions
• in culture, primary hepatocytes from mutant mice show increased content of enzymes involved in lipid metabolism and reduced lysosomal degradation of these enzymes
• although basal oxygen consumption rates are normal, mutant hepatocytes exhibit significantly reduced maximal mitochondrial respiratory capacity, fail to increase mitochondrial respiration in response to a lipogenic challenge and show lower rates of beta-oxidation in these conditions
• the VLDL secretion rate is significantly reduced in mutant livers
|
|
|
• after two i.p. injections of isoproterenol to induce peripheral lipolysis, mutant livers show a ~5-fold increase in TG content relative to control livers
|
|
|
• mutant mice exhibit lower basal levels of glycogen synthetase (GS)
• a higher percentage of GS is in an inactive phosphorylated state (pGS)
• however, GS is still efficiently activated, even at higher levels than in control mice, following stimulation of hepatic glycogenesis by insulin injection in overnight starved mice
|
|
|
• after 16 weeks on a high-fat diet (HFD; 60% calories from fat), mutant mice exhibit significantly larger livers than control mice
• mutant mice display enlarged livers
|
|
|
• mutant mice exhibit an increased liver weight relative to body weight
|
|
|
• biochemical analysis and PAS staining revealed a significant reduction of glycogen content in mutant livers
|
|
|
• after two i.p. injections of isoproterenol to induce peripheral lipolysis, mutant livers show a ~5-fold increase in TG content relative to control livers
|
|
|
• mutant hepatocytes contain an increased number and size of cytosolic lipid droplets (LDs), which become even more evident after starvation
• in the fed state, the major lipid species that accumulate in mutant livers are cholesterol esther and triacylglycerides (TG)
• after 24 hr of starvation, mutant livers also accumulate TG precursors, such as free fatty acids (FFAs) and diacylglycerol (DAG)
• after two i.p. injections of isoproterenol to induce peripheral lipolysis, mutant livers display more pronounced LD accumulation than control livers, with a ~5-fold increase in TG content, whereas cholesterol content remains unchanged
• after 16 weeks on a HFD, mutant livers exhibit more pronounced LD accumulation than control livers
|
|
|
• mutant mice display discolored livers
• after 16 weeks on a HFD, mutant mice exhibit significantly paler livers than control mice
|
|
|
• mutant livers exhibit a switch from carbohydrate synthesis and storage to carbohydrate hydrolysis and utilization
|
|
|
• liver apoptosis is significantly increased, as shown by TUNEL analysis
|
|
|
• significant decline in liver function as early as 4 months of age, as shown by the increased clearance time of zoxazolamine (a muscle relaxant metabolized by the liver), in a zoxazolamine-induced paralysis time assay
|
|
|
• after a 24 hr starvation, mutant mice show smaller adipocyte LDs in interscapular brown adipose tissue (BAT) than control mice
|
|
|
• after a 24 hr starvation, mutant mice show smaller adipocyte LDs in perigonadal WAT than control mice
|
|
|
• after a 24 hr starvation, mutant mice show reduced perigonadal white adipose tissue (WAT) weight than control mice
|
|
|
• fed mutants exhibit lower total-body fat mass (as a percent of body weight) than control mice; this is further accentuated after a 24 hr starvation
|
|
N |
• liver lysosomes show no differences in their content of mature hydrolases (e.g. cathepsin D), enzymatic activities (e.g. total liver and lysosomal beta-hexosaminidase activities), or stability of their membranes relative to control lysosomes
• steady state levels of integral autophagosome components and autophagy receptors are normal in mutant livers
• most autophagic vacuoles in mutant livers are autophagolysosomes, and the autophagosome/autophagolysosome ratio is similar to that in control mice
|
|
|
• mice are unable to internalize and degrade select proteins by chaperone-mediated autophagy (CMA)
• in vivo blockage of lysosomal proteolysis by i.p. injection of leupeptin revealed that GAPDH (a known CMA substrate) is no longer degraded in mutant liver lysosomes
• in contrast, lysosomal delivery and degradation of cytosolic proteins such as cyclophillin (a non-CMA substrate) is normal
|
|
|
• liver apoptosis is significantly increased, as shown by TUNEL analysis
|
|
|
• mutant livers display enhanced glucose uptake but reduced usage of glucose for glycogen synthesis
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice are born in the expected Mendelian ratio and survive to adulthood, unlike Mad2l1bptm1.2Itl homozygotes
|
|
• at 2 months of age, mice show hyperglycemia in the fed state
• surprisingly, blood glucose levels become normal by 6 months of age
• adeno-associated virus (AAV)-mediated expression of MAD2L1BP (but not of GFP) in the liver rescues the hyperglycemia phenotype
|
|
• at 2 months of age, mice show hyperinsulinemia in the fed state that is less severe than that in Insrtm1Khn/Insrtm1Khn
Speer6-ps1Tg(Alb-cre)21Mgn/Speer6-ps1+ mice
|
|
• at 2 months of age, serum triglyceride levels are moderately increased
|
|
• at 2 months of age, male mice develop glucose intolerance that is less severe than that in Insrtm1Khn/Insrtm1Khn
Speer6-ps1Tg(Alb-cre)21Mgn/Speer6-ps1+ mice
• AAV-mediated expression of MAD2L1BP (but not of GFP) in the liver rescues the glucose intolerance phenotype
|
|
• at E18.5, liver glycogen levels are decreased but to a much lesser extent than in Mad2l1bptm1.2Itl homozygotes, thus enabling survival
• at 2 months of age, liver glycogen levels are reduced but to a lesser extent than in Insrtm1Khn/Insrtm1Khn
Speer6-ps1Tg(Alb-cre)21Mgn/Speer6-ps1+ mice
• however, no liver developmental defects are noted at E18.5 or at 2 months of age
|
|
• at 2 months of age, male mice develop insulin intolerance that is less severe than that in Insrtm1Khn/Insrtm1Khn
Speer6-ps1Tg(Alb-cre)21Mgn/Speer6-ps1+ mice
• AAV-mediated expression of MAD2L1BP (but not of GFP) in the liver rescues the insulin intolerance phenotype
|
|
• at 2 months of age, hepatic triglyceride levels are decreased by about 50%
|
|
• insulin treatment fails to stimulate glycogen synthase activity (GS) in hepatocytes, unlike in wild-type hepatocytes
|
|
• at E18.5, liver glycogen levels are decreased but to a much lesser extent than in Mad2l1bptm1.2Itl homozygotes, thus enabling survival
• at 2 months of age, liver glycogen levels are reduced but to a lesser extent than in Insrtm1Khn/Insrtm1Khn
Speer6-ps1Tg(Alb-cre)21Mgn/Speer6-ps1+ mice
• however, no liver developmental defects are noted at E18.5 or at 2 months of age
|
|
• at 2 months of age, hepatic triglyceride levels are decreased by about 50%
|
|
• insulin receptor (IR) autophosphorylation and activating phosphorylation of AKT (pT308) are significantly reduced whereas inhibitory phosphorylation of GSK3 (pS9) is modestly reduced in whole-liver lysates from insulin-treated mice
• AAV-mediated expression of MAD2L1BP (but not of GFP) in the liver rescues the insulin signaling defects
|
|
• insulin-dependent glycogen synthase (GS) activation is abolished in hepatocytes
• freshly isolated primary hepatocytes display weakened and delayed IR autophosphorylation and AKT pT308 at multiple time points and over a wide range of insulin concentrations
|
|
• only 10% (1 out of 10) live hepatocytes is aneuploid relative to none (0 of 15) wild-type hepatocytes
• AAV-mediated expression of MAD2L1BP does not eliminate aneuploidy: 5% (2 of 39) hepatocytes are aneuploid vs only 2.5% (1 of 40) hepatocytes in the AAV-GFP control group
|
|
• hepatocytes show defective insulin endocytosis as a result of a reduced level of functional IR at the plasma membrane, due to premature internalization of IR prior to insulin stimulation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal numbers of hepatic NK, dendritic and B cells
• development and maintenance of NK T and T cells in the lymphoid organs is normal
|
|
• impaired fetal and neonatal B cell development
|
|
• intrahepatic lymphocytes
|
|
• in fetal and neonatal liver samples
|
|
• in the liver
|
|
• in the liver
|
|
• of NK T and invariant NK T (5-fold) cells in the liver
• however, the number of invariant NK T cells in the thymus and spleen is normal
|
|
• impaired hepatic invariant NK T cell maintenance
• however, development and maintenance of NK T and T cells in the lymphoid organs is normal
|
| N |
• mice exhibit normal numbers of hematopoietic progenitors
|
|
• impaired fetal and neonatal B cell development
|
|
• intrahepatic lymphocytes
|
|
• in fetal and neonatal liver samples
|
|
• in the liver
|
|
• in the liver
|
|
• of NK T and invariant NK T (5-fold) cells in the liver
• however, the number of invariant NK T cells in the thymus and spleen is normal
|
|
• impaired hepatic invariant NK T cell maintenance
• however, development and maintenance of NK T and T cells in the lymphoid organs is normal
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• decrease in the number of nuclei containing 2 or more lipid droplets compared to mutant mice wild-type for Tor1a, 7 +/- 3% compared to 64 +/- 5%
|
|
• grossly white livers
|
|
• decreased triglyceride, apoB100, and apoB48 secretion rates
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• decrease in the number of nuclei containing 2 or more lipid droplets compared to mutant mice wild-type for Tor1a, 33 +/- 7% compared to 64 +/- 5%
|
|
• grossly white livers
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Decreased glycogen liver content in Gys2tm1.1Pro/Gys2tm1.1Pro Speer6-ps1Tg(Alb-cre)21Mgn/0 mice
|
• fed mice exhibit reduced exercise capacity compared with control Gys2tm1.1Pro homozygotes
|
|
• during a fast, mice exhibit a more acute increase in ketone bodies than in similarly treated control Gys2tm1.1Pro homozygotes
|
|
• in fed and fasted states, mice exhibit reduced circulating glucose levels compared with similarly treated control Gys2tm1.1Pro homozygotes
• mice enter a fasted state quicker than similarly treated control Gys2tm1.1Pro homozygotes
|
|
• under fed condition
|
|
• mice exhibit enhanced gluconeogenesis compared with control Gys2tm1.1Pro homozygotes
|
|
• glycogen liver content is reduced 94% compared to in control Gys2tm1.1Pro homozygotes
• exercised mice exhibit a greater decrease in muscle glycogen levels compared with control Gys2tm1.1Pro homozygotes
• however, glycogen content in the skeletal muscle and kidney is normal
|
|
• fasting mice fail to exhibit a change in triglyceride levels unlike fasted control Gys2tm1.1Pro homozygotes
|
|
• at 7 and 15 months
|
|
• heart glucose uptake is lower than in control Gys2tm1.1Pro homozygotes
|
|
• at 7 and 15 months
|
|
• heart glucose uptake is lower than in control Gys2tm1.1Pro homozygotes
|
|
• fed mice exhibit reduced exercise capacity compared with control Gys2tm1.1Pro homozygotes
|
|
• heart glucose uptake is lower than in control Gys2tm1.1Pro homozygotes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 70-80% die by 4 weeks and all die by 6 weeks of age
|
|
• mice start to die around 2 weeks of age
|
|
• mean liver weight-to-body weight ratio is increased
|
|
• marker analysis shows no, or rare, bile ducts in the periportal zone of the liver
|
|
• liver is yellowish
• targeting of tight junctions and apical molecules is disrupted in the liver
• marker analysis indicates that liver zonation is perturbed
• however, no liver inflammation or fibrosis are seen
|
|
• the lumina of the sinusoidal vessels are not clear
• marker analysis shows that sinusoidal vessels in the liver are injured
|
|
• mean liver weight-to-body weight ratio is increased
|
|
• the hepatic cords are not well-organized in the liver
|
|
• normal bile canaliculi are hardly seen
|
|
• individual hepatocytes appear slightly swollen with vacuole-like structures inside
• hepatocytes exhibit ectopic luminal structures around their basolateral domains
• hepatocyte cellular polarity is disrupted, with an unclear distinction between the apical and basolateral plasma membrane domains
|
|
• mice show disruption of the hepatic barrier
• bile transport into bile canaliculi is diminished
|
|
• mice show an increase in Ki-67+ hepatocytes, indicating increased hepatocyte proliferation
|
|
• mice show increased levels of total bilirubin and direct bilirubin
|
|
• mice show increased levels of alkaline phosphatase
• however, gamma-glutamyl transferase levels are normal
|
|
• mice show increased levels of bile acids
|
|
• the lumina of the sinusoidal vessels are not clear
• marker analysis shows that sinusoidal vessels in the liver are injured
|
|
• mice show an increase in Ki-67+ hepatocytes, indicating increased hepatocyte proliferation
|
|
• marker analysis shows no, or rare, bile ducts in the periportal zone of the liver
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| progressive familial intrahepatic cholestasis 4 | DOID:0070224 |
OMIM:615878 |
J:306936 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• reduced nonheme iron level in liver mitochondria when fed low-iron or regular chow
• reduced nonheme iron level in liver when fed low-iron chow
|
|
• reduced nonheme iron level in liver mitochondria when fed low-iron or regular chow
• reduced nonheme iron level in liver when fed low-iron chow
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• reduced liver cell proliferation 48h after partial hepatectomy
|
|
• significant reduction in OXPHOS protein levels in liver
|
| N |
• mice born at expected Mendelian ratio
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• reduced nonheme iron level in liver mitochondria when fed low-iron chow
• reduced nonheme iron level in liver when fed low-iron chow
|
|
• reduced nonheme iron level in liver mitochondria when fed low-iron chow
• reduced nonheme iron level in liver when fed low-iron chow
|
|
• significant reduction in OXPHOS protein levels in liver
|
| N |
• mice born at expected Mendelian ratio
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• reduced nonheme iron level in liver mitochondria when fed low-iron or regular chow
• reduced nonheme iron level in liver when fed low-iron chow
|
|
• reduced liver cell proliferation 48h after partial hepatectomy
|
|
• reduced nonheme iron level in liver mitochondria when fed low-iron or regular chow
• reduced nonheme iron level in liver when fed low-iron chow
|
|
• significant reduction in OXPHOS protein levels in liver
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice show normal total and direct bilirubin levels, bile acids, and alkaline phosphatase levels, and normal livers
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• modest increases in cell death of hepatocytes
|
|
• increased proliferation index at 3 months of age as measure by elevated levels of BrdU incorporation
|
|
• at 2 months of age, large numbers of small periductal cells are visible that infiltrate the liver parenchyma
• at 3 months of age, small periductal cells surround the hepatic plates
|
|
• an irregular arrangement of hepatocytes that obscures the normal radiating pattern of liver sinusoids
|
|
• a 2-fold increase in liver mass relative to total body mass at 1 month of age and a 3-fold increase by 3 months of age
|
|
• hepatocytes exhibit a "clear cell" phenotype
|
|
• tumors are detectable in some mice at 3 months of age and in all mice at 4 months of age
• livers are highly enlarged and have multiple focal tumors visible at 5-6 months of age
• disorganized parenchyma with the majority of the liver exhibiting a dysplastic partially transformed phenotype
|
|
• the histopathology of tumor nodules is consistent with a diagnosis of hepatocellular
carcinoma
|
|
• tumors are detectable in some mice at 3 months of age and in all mice at 4 months of age
• livers are highly enlarged and have multiple focal tumors visible at 5-6 months of age
• disorganized parenchyma with the majority of the liver exhibiting a dysplastic partially transformed phenotype
|
|
• the histopathology of tumor nodules is consistent with a diagnosis of hepatocellular
carcinoma
|
|
• an irregular arrangement of hepatocytes that obscures the normal radiating pattern of liver sinusoids
|
| N |
• despite morphological liver changes, no increase in serum alanine aminotransferase or aspartate aminotransferase levels are detected at 2 months of age
|
|
• modest increases in cell death of hepatocytes
|
|
• increased proliferation index at 3 months of age as measure by elevated levels of BrdU incorporation
|
|
• a 2-fold increase in liver mass relative to total body mass at 1 month of age and a 3-fold increase by 3 months of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increased BrdU incorporation
|
|
• 10% increase in liver size by 4months of age
|
|
• mice at 13-14 months of age develop large liver tumors that are hepatocellular carcinoma and
cholangiocarcinoma like
|
|
• mice at 13-14 months of age develop large liver tumors that are hepatocellular carcinoma and
cholangiocarcinoma like
|
|
• mice at 13-14 months of age develop large liver tumors that are hepatocellular carcinoma and
cholangiocarcinoma like
|
|
• increased BrdU incorporation
|
|
• 10% increase in liver size by 4months of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice do not accumulate plasma triglycerides
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• normal lactate-induced Mg2+ uptake in hepatocyte mitochondria in vitro
• normal lactate-induced Mg2+ depletion in hepatocyte ER in vitro
|
| N |
• normal lactate-induced Mg2+ uptake in hepatocyte mitochondria in vitro
• normal lactate-induced Mg2+ depletion in hepatocyte ER in vitro
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• mice weigh less than controls, however liver weights are unchanged
|
|
|
• rate of sterol synthesis in the liver is decreased by 59%
• rate of fatty acid synthesis in the liver is decreased by 68%
|
|
|
• plasma cholesterol level is reduced by 68%
|
|
|
• plasma triglyceride level is reduced by 50%
|
|
|
• liver cholesterol level is reduced by 20%
• dietary supplementation with 0.2% cholesterol increased liver cholesterol concentrations to control levels
|
|
|
• liver triglyceride level is reduced by 76%
• triglyceride secretion rate from liver is reduced by 29%
|
|
|
• liver cholesterol level is reduced by 20%
• dietary supplementation with 0.2% cholesterol increased liver cholesterol concentrations to control levels
|
|
|
• liver triglyceride level is reduced by 76%
• triglyceride secretion rate from liver is reduced by 29%
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• HDL levels are reduced by 80%
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• by P5
|
|
• not well organized
|
|
• hepatoblasts fail to differentiate
|
|
• yellowish liver
|
|
• mice fail to accumulate glycogen unlike control mice
|
|
• small during the first 4 days after birth
|
|
• at P1 or P2
|
|
• mice fail to accumulate glycogen unlike control mice
|
|
• not well organized
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• unlike homozygous null mice, mice with loss of expression in the liver after birth are viable
|
|
• at 6 - 8 weeks of age, but not at P17, the number of proliferating cells is increased
|
|
• by P28 livers are hypertrophic
|
|
• ratio of liver weight to body weight is increased to about 25 - 30% compared to about 5% in heterozygous mice
|
|
• dramatic depletion of glycogen in hepatocytes
|
|
• up to a 17-fold increase in triglyceride levels in the liver at P17
|
|
• cells with abnormal cytoplasm are apparent at P17
|
|
• accumulation of lipid droplets
• elevated triglyceride levels at P17
• treating mice with rapamycin reduces neutral lipid accumulation but does not alter the increase in liver size
|
|
• by P28
|
|
• increases with age
|
|
• by P17
|
|
• present by 6 weeks of age but not at P17
• at 10 weeks of age fasting glucose level is almost 2-fold lower than in control littermates
• however, glucose tolerance is not significantly different from controls
|
|
• slightly lower at P17
|
|
• dramatic decrease by P28 which persists as mice age
|
|
• dramatic depletion of glycogen in hepatocytes
|
|
• increases with age
|
|
• increases with age
|
|
• increases with age
|
|
• up to a 17-fold increase in triglyceride levels in the liver at P17
|
|
• by 4 - 6 weeks of age
|
|
• by P28 livers are hypertrophic
|
|
• ratio of liver weight to body weight is increased to about 25 - 30% compared to about 5% in heterozygous mice
|
|
• visibly leaner with a substantial reduction in visceral adipose tissue by 6 - 8 weeks of age
|
|
• at 6 - 8 weeks of age, but not at P17, the number of proliferating cells is increased
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice become moribund at 30 days of age and are euthanized
|
|
• although normal at birth, mice become growth retarded after 14 days of age
|
|
• glutathione levels in the liver are about 37% of normal at 14 days of age
• glutathione levels in plasma are extremely low at 14 days of age
|
|
• plasma levels are dramatically elevated by 28 days of age
|
|
• plasma levels are dramatically elevated by 28 days of age
|
|
• vacuolated hepatocytes are diffusely present at 21 days of age
• both macrovesicular and microvesicular vacuoles are found
• vacuoles contain neutral lipid
• scattered instances of single cell death
• increased number of binucleate hepatocytes
|
|
• increasing steatosis from 21 days (26%) to 28 days of age (69%)
|
|
• loss of lamellar rough endoplasmic reticulum in hepatocytes by 28 days of age
• replaced by small vesicles lacking ribosomes
|
|
• 20% of mitochondria are morphologically abnormal in hepatocytes at 21 days of age
|
|
• mitochondrion number in hepatocytes is 42% of control numbers at 14 days and 16% at 28 days of age
|
|
• mitochondrial respiratory control ratios in hepatocytes are reduced at 21 days
• decreased oxygen consumption at state 3 respiration
• poorly coupled at 25 and 28 days
• decreased membrane potentials
• reduced liver ATP
• increased lipid peroxidation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• secrete 70% less insulin in response to glucose stimulus
|
|
• 10% increase in fed blood glucose concentration
|
|
• post-absorptive (fed) plasma insulin concentrations twice that of controls
|
|
• glucose turnover and glucose infusion rates during hyperglycemic clamp are reduced
|
|
• net hepatic glycogen synthesis is reduced by about 90% during hyperglycemic clamp studies
|
|
• mild insulin resistance
|
|
• secrete 70% less insulin in response to glucose stimulus
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| maturity-onset diabetes of the young type 2 | DOID:0111100 |
OMIM:125851 |
J:51826 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit largely normal glucose metabolism whether fed a standard or high fat diet
|
|
• slight after 30 minutes in an oral glucose tolerance test in mice fed a standard diet
• slight after 60 minutes in an oral glucose tolerance test in mice fed a high fat diet
|
| N |
• mice exhibit normal weight and growth whether fed a standard or high fat diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• plasma HDL levels are reduced by 90%
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice are obtained at a slightly lower than the expected number (10 versus 14.5) based on the Mendelian ratio; time of lethality is not specified
|
|
• mice attain ~40% of normal weight at 3 weeks of age
|
|
• mice appear normal at birth but fail to thrive, similar to Bub1btm1Jvd homozygotes
|
|
• mice exhibit hypoglycemia in the fed state, similar to Bub1btm1Jvd homozygotes and opposite to Mad2l1bptm1.1Itl/Mad2l1bptm1.1Itl Speer6-ps1Tg(Alb-cre)21Mgn/Speer6-ps1+ mice
|
|
• mice exhibit increased glucose tolerance, similar to Bub1btm1Jvd homozygotes and opposite to Mad2l1bptm1.1Itl/Mad2l1bptm1.1Itl Speer6-ps1Tg(Alb-cre)21Mgn/Speer6-ps1+ mice
|
|
• mice exhibit increased insulin sensitivity, similar to Bub1btm1Jvd homozygotes and opposite to Mad2l1bptm1.1Itl/Mad2l1bptm1.1Itl Speer6-ps1Tg(Alb-cre)21Mgn/Speer6-ps1+ mice
|
|
• at 2 months of age, the cell and nuclear sizes of hepatocytes in male mice are larger than those in single knockout mice
|
|
• mice exhibit an increased percentage of hepatocytes with 8N or greater DNA content, indicating a striking ploidy change
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal mortality
|
| N |
• mice exhibit normal liver morphology
|
|
• mild reduction in respiratory capacity in liver mitochondria
• however, a diet supplemented with dietary ubiquinine rescues respiratory chain function
|
|
• mild reduction in respiratory capacity in liver mitochondria
• however, a diet supplemented with dietary ubiquinine rescues respiratory chain function
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• on a normal diet liver levels are about 40% lower than in wild-type
|
|
• after being on a fat free diet for 10 days lipid accumulation in the liver is 66% lower than in wild-type; however fat pad weight is similar to wild-type
• however, when fed a high fat high carbohydrate diet fatty liver development is similar to wild-type
|
|
• in cultured hepatocytes the rate of fatty acid synthesis is about 50% of wild-type
• liver acetyl-CoA carboxylase activity is reduced by about 75%
|
|
• on a high fat high carbohydrate but not on a standard chow diet
|
|
• on a high fat high carbohydrate diet blood glucose is increased to 185 +/- 7 mg/dl compared to 155 +/-8 mg/dl for wild-type mice
• however, on a standard diet blood glucose levels are similar
|
|
• after being on a fat free diet for 10 days insulin levels are increased but blood glucose is similar to wild-type
|
|
• on a high fat high carbohydrate nonesterified fatty acid levels are increased by about 30% compared to wild-type mice
|
|
• after being on a fat free diet for 10 days liver levels of saturated and monounsaturated fatty acids are significantly lower than in wild-type; however overall liver lipid composition is similar
|
|
• on a normal diet or when fed a fat free diet for 10 days
|
|
• on a normal diet liver levels are about 40% lower than in wild-type
|
|
• liver acetyl-CoA carboxylase activity is reduced by about 75%
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• bile contains higher concentrations of tauromuricholic acids, taurochenodeoxycholic acid, alpha/omega muricholic acid, and beta-muricholic acid and lower concentrations of taurocholic acid and taurodeoxycholic acid compared to bile in wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in mice fed a 0.05% cholesterol diet
|
|
• in mice fed a 0.05% cholesterol diet
|
|
• in mice fed a 0.1% or 0.5% dietary cholesterol
|
|
• regardless of dietary cholesterol percentage
|
|
• total cholesterol and cholesteryl ester regardless of dietary cholesterol percentage
• free cholesterol when fed a 0.5% cholesterol diet
|
|
• when fed a 0.5% cholesterol diet
|
|
• total cholesterol and cholesteryl ester regardless of dietary cholesterol percentage
• free cholesterol when fed a 0.5% cholesterol diet
|
|
• when fed a 0.5% cholesterol diet
|
| N |
• mice exhibit normal cholesterol absorption
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• according to Krt19 activity
|
|
• significant lymphocyte and macrophage infiltration
• increased serum levels of Il6, Il18, Il10, Ifng, and Tnf
|
|
• more multinucleate hepatocytes and smaller hepatocytes when fed 0.5% sodium cholate-supplemented diet
|
|
• when fed 0.5% sodium cholate-supplemented diet
• when fed standard chow
|
|
• increased levels of Col1a1, Col3a1 and Tgfb
• exacerbated when fed 0.5% sodium cholate-supplemented diet
|
|
• yellow serum at age 2 months on standard chow
• when fed 0.5% sodium cholate-supplemented diet
|
| N |
• serum gamma-glutamyl transferase levels
• plasma creatinine, blood urea nitrogen, and uric acid levels on normal chow or 0.5% sodium cholate-supplemented diet
|
|
• exacerbated when fed 0.5% sodium cholate-supplemented diet
• approximately 15-fold higher serum total bilirubin (TBIL) levels
• mainly increase in direct bilirubin (DBIL) levels; indirect bilirubin (IBIL) levels only slightly increased
|
|
• exacerbated when fed 0.5% sodium cholate-supplemented diet
|
|
• exacerbated when fed 0.5% sodium cholate-supplemented diet
|
|
• approximately 20-fold higher serum total bile acid (TBA) levels
• dramatically increased serum unconjugated and conjugated bile acid levels; only small changes in hepatic and biliary bile salt species
• exacerbated when fed 0.5% sodium cholate-supplemented diet
|
|
• elevated plasma Alpl levels
• exacerbated when fed 0.5% sodium cholate-supplemented diet
|
| N |
• cellular morphology of heart, kidney, lung, spleen, muscle, pancreas, and intestine when fed regular chow or 0.5% sodium cholate-supplemented diet
|
|
• according to Krt19 activity
|
|
• significant lymphocyte and macrophage infiltration
• increased serum levels of Il6, Il18, Il10, Ifng, and Tnf
|
|
• when fed 0.5% sodium cholate-supplemented diet
|
|
• when fed 0.5% sodium cholate-supplemented diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Atherosclerosis lesion area is increased in Ldlrtm1Her/Ldlrtm1Her Nr1h3tm1.1Djm/Nr1h3tm1.1Djm Speer6-ps1Tg(Alb-cre)21Mgn/0 mice and TO901317 treatment reduces these lesions
|
• by 4 weeks in mice fed a western diet
|
|
• mice fed a western diet and treated with T0901317 (an Lxr/Nr1h3 agonist) exhibit impaired reverse cholesterol transport compared with control mice
|
|
• by 4 weeks in mice fed a western diet
|
|
• in mice fed a western diet at the conclusion of the experiment
|
|
• mice fed a western diet and treated with T0901317 (an Lxr/Nr1h3 agonist) fail to exhibit a change in plasma lipid levels or an increase in fecal excretion of macrophage-derived sterols but an increase in hepatic sterols compared with control mice
• however, treatment with T0901317 reduces atherosclerosis as in controls
|
|
• in mice fed a western diet at the conclusion of the experiment
|
|
• mice fed a western diet exhibit increase in lesion size as detected by macrophage staining compared with control mice
• however, collagen staining or lesions is normal and treatment with T0901317 reduces atherosclerosis as in controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• when fed a high cholesterol diet with cholic acid diet
|
|
• either when fed a high cholesterol diet with cholic acid diet or an iodine-deficient diet compared to similarly treated Nr0b2tm1Mjev homozygotes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• decrease in hepatocyte size
|
|
• about a 40% decrease in liver mass compared to controls
|
|
• decrease in liver protein content
• fasting does not decrease the size of the liver, unlike in controls
|
|
• at early times after refeeding compared to wild-type controls
• feeding mice sodium octanoate after a fast results in prolonged elevation of ketone levels
• aged mice do not display a reduction in ketone production during fasting unlike in aged wild-type controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice treated with T0901317 (an Lxr/Nr1h3 agonist) exhibit an attenuated increase in plasma triglycerides, hepatic triglycerides, biliary cholesterol, biliary cholesterol secretion and fecal neutral sterols but an attenuated decrease in CAMCA bile acid composition and cholesterol absorption compared with control mice
|
|
• in mice fed a 2% cholesterol diet
|
|
• mice treated with T0901317 (an Lxr/Nr1h3 agonist) exhibit an attenuated increase in plasma triglycerides and cholesterol, hepatic triglycerides, biliary cholesterol, biliary cholesterol secretion and fecal neutral sterols and attenuated decrease in CAMCA bile acid composition, cholesterol absorption and hepatic cholesterol compared with control mice
|
|
• in mice fed a 2% cholesterol diet
|
|
• in mice fed a 2% cholesterol diet
|
|
• in mice fed a 2% cholesterol diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in mice fed standard chow at 6 weeks of age but not 9, 12, 34, 46 and 58 weeks
• in mice fed a high copper diet at 28, 40 and 52 weeks
|
|
• in mice fed standard chow at 6 weeks of age but not 9, 12, 34, 46 and 58 weeks
• in mice fed a high copper diet at 28, 40 and 52 weeks
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal postnatal liver and body growth and function
|
|
• only a few hepatocytes attach with atypical morphology after seeding
|
|
• isolated primary hepatocytes show decreased viability immediately upon isolation, prior to plating (<70% viable cells) compared to controls or other mutant genotypes
|
|
• injection of CCL4 to the liver induces a greater degree of liver injury in mice compared to control or individual single knockout mice; advanced bridging central injury is induced in livers
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice fed a high-cholesterol diet for 12 weeks exhibit a similar body and liver weight as single Ldlr homozygotes and do not develop increased atherosclerosis
|
|
• reverse cholesterol transport analysis indicates an increase in fecal sterol content compared to single Ldlr homozygote
|
|
• reverse cholesterol transport analysis indicates an increase in fecal sterol content compared to single Ldlr homozygotes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• no histologic differences are detected
|
|
• mice show no significant differences from wild-type in body or organ weights
|
|
• the paternally-inherited Igf2r allele is normally silenced through genomic imprinting so embryos inheriting the floxed Igf2r allele maternally are functionally liver-specific homozygous knockouts
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal postnatal liver and body growth and function
|
|
• after attachment to culture dishes, hepatocytes are elongated with process formation and cell separation compared to wild-type cells which have a cobblestone epithelial morphology
|
|
• hepatocytes express much higher levels of vimentin (mesenchymal marker) compared to control or Smad3 mutant cells
|
|
• in culture, untreated cells exhibit ~3-fold greater proliferation compared to controls and Smad3 hepatocytes; after TGFbeta treatement, cells show reduced proliferation compared to controls
• in CCL4-injured livers, cell proliferation is higher at earlier time points than in controls or Smad3-deficient livers
|
|
• hepatocytes dedifferentiate spontaneously to acquire mesenchymal and promigratory features in culture
|
|
• compared to wild-type cells which cannot migrate to the wound area in a scratch-wound in vitro assay after 24 hours or only partial cover area when treated with TGFbeta, mutant cells cover the entire scratch area in absence of TGFbeta
|
|
• in culture, untreated cells exhibit ~3-fold greater proliferation compared to controls and Smad3 hepatocytes; after TGFbeta treatement, cells show reduced proliferation compared to controls
• in CCL4-injured livers, cell proliferation is higher at earlier time points than in controls or Smad3-deficient livers
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• slight but significant increase in the percentage of Ki67-positive hepatocytes from 14 week old mice compared to age-matched control mice
|
|
• slight but significant increase in the percentage of Ki67-positive hepatocytes from 14 week old mice compared to age-matched control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• the number of Ki67-positive hepatocytes is 1.5-fold greater compared to age-matched control mice but 1.5 fold less than hepatocytes from homozygous mice conditionally null for Trim24 in the liver
|
|
• the number of Ki67-positive hepatocytes is 1.5-fold greater compared to age-matched control mice but 1.5 fold less than hepatocytes from homozygous mice conditionally null for Trim24 in the liver
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in fasted and fed mice
• following insulin injection
|
|
• in fasted mice
|
|
• in fasted mice
|
|
• mice exhibit increased ability to clear glucose during a glucose tolerance test compared with wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• after diethylnitrosamine (DEN) and phenobarbitol (PB) treatment, no adenomas were observed in liver sections from these mice at 23, 33 and 50 weeks of age in contrast to controls
|
|
• after diethylnitrosamine (DEN) and phenobarbitol (PB) treatment, no adenomas were observed in liver sections from these mice at 23, 33 and 50 weeks of age in contrast to controls
|
|
• hepatocyte hypertrophy and compensatory increase in liver size at 7 days after partial hepatectomy
(J:81015)
• hypertrophy of hepatocytes was observed at 23 weeks after diethylnitrosamine (DEN) and phenobarbitol (PB) treatment; hepatocytes exhibited a significant reduction in DNA replication and mitosis
(J:89472)
|
|
• after diethylnitrosamine (DEN) and phenobarbitol (PB) treatment, no adenomas were observed in liver sections from these mice at 23, 33 and 50 weeks of age in contrast to controls
|
|
• after partial hepatectomy, hepatocytes exhibited a significant reduction in DNA replication and mitosis; changes in expression levels of cell cycle proteins were observed
|
|
• after diethylnitrosamine (DEN) and phenobarbitol (PB) treatment, no adenomas were observed in liver sections from these mice at 23, 33 and 50 weeks of age in contrast to controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 65% reduction in the percentage of bodyfat in mice fed a zero fat diet
|
|
• 50% reduction in fat pad/BW ratio in mice fed a zero fat diet
|
|
• there is a 40% reduction in blood glucose levels after a 4 hour fast in mice fed a zero fat diet
|
|
• there is a 50% increase in glucagon levels after a 4 hour fast in mice fed a zero fat diet
|
|
• there is a two fold reduction in circulating insulin after a 4 hour fast in mice fed either a chow diet or a no fat diet
|
|
• two fold reduction in mice fed a zero fat diet
|
|
• 50% increase in nonesterifed fatty acids in serum of mice fed a zero fat diet
|
|
• about 40% reduction in cholesterol found in the liver
|
|
• in mice fed a high carbohydrate diet with no fat, the level of palmitate in the liver is significantly reduced after an overnight fast
• there is also a 3 fold increase in the liver of the palmitate precursor malonyl-CoA
there is also a 3 fold increase in the liver of the palmitate precursor malonyl-CoA
there is also a 3 fold increase in the liver of the palmitate precursor malonyl-CoA
|
|
• modest increase in levels in mice fed a zero fat diet
|
|
• 35% increase in weight in mice fed a zero fat diet
|
|
• about 40% reduction in cholesterol found in the liver
|
|
• pale appearance of liver in mice fed a zero fat diet
|
|
• 35% increase in weight in mice fed a zero fat diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• viable and fertile
|
| N |
• indistinguishable from controls
|
| N |
• plasma cholesterol and triglyceride levels similar to controls
|
|
• by 2 weeks of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at 10-12 months, enlarged livers with multiple tumors were seen in 100% (12/12) mutant mice
|
|
• at 10-12 months, enlarged livers with multiple tumors were seen in 100% (12/12) mutant mice
|
|
• at 4 weeks
|
|
• infiltration of inflammatory cells are seen in 4 weeks old mutant mice liver
|
|
• note: apoptotic cells and necrosis are seen in 4 weeks old mutant mice liver
|
|
• infiltration of inflammatory cells are seen in 4 weeks old mutant mice liver
|
|
• at 4 weeks, fatty vacuolated cells in liver had a 3-fold elevation in triglyceride levels
• lipid accumulation was also seen in cultures of primary hepatocytes derived from mutant mice
|
|
• pericentral and pericellular fibrosis was seen in older animals
|
|
• at 10-12 months, enlarged livers with multiple tumors were seen in 100% (12/12) mutant mice
|
|
• at 10-12 months, enlarged livers with multiple tumors were seen in 100% (12/12) mutant mice
|
|
• note: apoptotic cells and necrosis are seen in 4 weeks old mutant mice liver
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| hepatocellular carcinoma | DOID:684 |
OMIM:114550 |
J:97188 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice are 10-15% smaller than controls
|
|
• shorter crown-anus length than controls
|
|
• both fed and fasted/refed mutant mice show significantly lower levels of liver glycogen than controls
• fasted mice show similar levels of liver glycogen to controls
|
|
• significant elevation consistent with decreased insulin levels
|
|
• a decrease in serum insulin after glucose challenge occurs in contrast to an increase in control mice
• insulin clearance appears to be unaffected
• isolated pancreatic islets are defective in the ability to secrete insulin by glucose stimulation at all concentrations tested ; such islets contain more isulin than control islets, suggesting that the defect is in secretion and not in synthesis or storage
|
|
• fasting and fed state blood glucose levels are 25% higher than controls
• mice that are fasted then refed for 6 hours exhibit normal blood glucose levels
|
|
• fasting insulin levels are lower than controls
• slight elevation is seen after a 6 hour refeeding period
• normal insulin sensitivity is seen at two different doses of insulin
|
|
• mutant animals exhibit an impaired ability to remove glucose from the bloodstream after intraperitoneal glucose injection
|
|
• reductions in the levels of fructose-2,6-bisphosphate in the fed state; lower levels are thought to promote gluconeogenesis rather than glycolysis
• in the fed state, level of glucokinase transcripts are reduced; glucokinase regulates glycolysis in the liver
|
|
• both fed and fasted/refed mutant mice show significantly lower levels of liver glycogen than controls
• fasted mice show similar levels of liver glycogen to controls
|
|
• a decrease in serum insulin after glucose challenge occurs in contrast to an increase in control mice
• insulin clearance appears to be unaffected
• isolated pancreatic islets are defective in the ability to secrete insulin by glucose stimulation at all concentrations tested ; such islets contain more isulin than control islets, suggesting that the defect is in secretion and not in synthesis or storage
|
| N |
• no differences in the percent adiposity (fat pad weight by total body weight) is detected
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• hepatocyte numbers are extremely low at 4 days of age however
|
|
• ductal plate cells persist to 90 days unlike controls where they are lost by 2 weeks of age
|
|
• biliary epithelial cells form ectopic tubular structures in lobules at 4 days of age
• some ectopic structures have lumina while others are disorganized
• most ectopic structures are lost by 10 days of age
• increased number of bile ducts relative to controls at 90 days of age
|
|
• numbers are extremely low at 4 days of age
|
|
• ductal plate cells persist to 90 days unlike controls where they are lost by 2 weeks of age
|
|
• biliary epithelial cells form ectopic tubular structures in lobules at 4 days of age
• some ectopic structures have lumina while others are disorganized
• most ectopic structures are lost by 10 days of age
• increased number of bile ducts relative to controls at 90 days of age
|
|
• hepatocyte numbers are extremely low at 4 days of age however
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• many pups die perinatally
|
|
• fewer than the expected Mendelian ratio of pups is seen at weaning (only 17 out of 277 total pups)
|
|
• mice fed a high-fat diet are slightly leaner than wild-type mice, although both show hepatic steatosis
|
|
• pups are smaller at 2 days of age
• surviving mice have reduced body mass at 1 month of age, however by 4 months of age, mice weight the same as wild-type mice
|
|
• 30% increase in apoptosis in livers at 1 month of age
|
|
• reduction in the number of binuclear hepatocytes and tetraploidy suggest impaired hepatic differentiation and maturation
• livers show continued presence of hematopoietic cells at 1 month of age unlike in wild-type mice which show only residual CD45-positive hematopoietic cells, however, numbers of circulating blood cells are normal indicating a defect in hepatocyte maturation rather than increase in extramedullary hematopoiesis
|
|
• livers of surviving mice exhibit a roughened surface and multiple small nodules
• architecture of the liver is disturbed with large irregular hepatocytes, compressed sinusoidal spaces and bile canaliculi and clusters of small hematopoietic cells
• decrease in lipid droplets in the liver of 1 month old mice
|
|
• compressed sinusoidal spaces
|
|
• 60% decrease in stored glycogen in the liver
|
|
• decrease in cholesterol in the liver at 1 month of age but not at 4 months of age
|
|
• mice fed a high-fat diet do not show an increase in hepatic triglyceride levels as is seen in wild-type mice
|
|
• compressed bile canaliculi
|
|
• hepatocytes are larger with irregularly sized nuclei and dense mitotic figures
• reduction in the number of binuclear hepatocytes and tetraploidy suggesting impaired hepatic differentiation and maturation
|
|
• surviving mice have smaller livers at 1 month of age
|
|
• surviving mice have pale livers at 1 month of age
|
|
• decrease in fatty acid oxidation in the liver
|
|
• mice fed a high-fat diet are slightly leaner than wild-type mice, although both show hepatic steatosis
|
|
• mice exhibit fasting-induced hypoglycemia at 1 month of age however, fasting insulin levels are normal
• by 4 months of age, fasting blood glucose levels are normal
|
|
• serum cholesterol is lower at 1 month of age on a normal diet and at 4 months of age on the high-fat diet
|
|
• at 1 month of age
|
|
• serum triglyceride levels are lower on a normal diet and are unchanged on a high-fat diet
|
|
• total serum protein is decreased due to a 30% decrease in serum albumin
• however, blood urea nitrogen, calcium, and creatinine are normal
|
|
• glucose tolerance tests at 4 months of age in mice fed a low-fat diet for 12 weeks show decreased glucose at 15 min but normal values at subsequent times
|
|
• 60% decrease in stored glycogen in the liver
|
|
• insulin tolerance tests at 4 months of age in mice fed a low-fat diet for 12 weeks show increased insulin sensitivity and an inability to correct insulin-induced hypoglycemia
• mice fed a high-fat diet for 12 weeks show increased insulin sensitivity compared to wild-type mice, with a greater drop in blood glucose during the insulin tolerance test
|
|
• decrease in cholesterol in the liver at 1 month of age but not at 4 months of age
|
|
• mice fed a high-fat diet do not show an increase in hepatic triglyceride levels as is seen in wild-type mice
|
|
• compressed sinusoidal spaces
|
|
• the rough endoplasmic reticulum (ER) is dilated in the liver, indicating ER stress
|
|
• 30% increase in apoptosis in livers at 1 month of age
|
|
• decrease in fatty acid oxidation in the liver
|
|
• impaired thymic development
|
|
• impaired thymic development
|
|
• impaired thymic development
|
|
• impaired kidney development
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• accumulation of beta-aminoisobutyric acid (BAIB) after 24 hours of starvation
• severely impaired production of ketone body beta-hydroxybutyrate after 24 hours of starvation
• increased lipid droplet levels in liver after 24 hours of starvation
|
|
• increased levels of proline, serine, threonine, methionine, and lysine in serum after 24 hours of starvation
|
|
• increased lysine level in serum after 24 hours of starvation
|
|
• increased methionine level in serum after 24 hours of starvation
|
|
• increased proline level in serum after 24 hours of starvation
|
|
• increased serine level in serum after 24 hours of starvation
|
|
• increased threonine level in serum after 24 hours of starvation
|
|
• after 24 hours of starvation
|
|
• slight increase in serum at age 8 weeks
|
| N |
• no liver fibrosis or inflammation
|
|
• mitochondrial clustering in liver at age 8 weeks
|
|
• increased lipid droplet levels in liver after 24 hours of starvation
• depletion of alanine-glyoxylate aminotransferase 2 (Agxt2) after 24 hours of starvation
• severely impaired production of ketone body beta-hydroxybutyrate after 24 hours of starvation
• accumulation of beta-aminoisobutyric acid (BAIB) after 24 hours of starvation
|
|
• mitochondrial clustering in liver at age 8 weeks
|
|
• trend to increase in apoptotic cells in liver at age 8 weeks
|
|
• reduction in rate of maximal respiration after dissipation of membrane potential with carbonyl cyanide m-chlorophenyl hydrazone (CCCP)
|
|
• in liver after 24 hours of starvation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice show a reduction of plasma coagulation factor V (FV) activity and a reduction in plasma FV antigen level
• however plasma coagulation factor VIII (FVIII) levels are normal
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal alanine and aspartate transaminase levels, glucose and insulin tolerance
|
|
• hepatic and whole-body
|
|
• after 9 weeks on a high-fat diet
|
|
• in mice fed standard chow or a high-fat diet
|
|
• slightly in mice fed normal chow
• fasting lactate in mice fed a high-fat diet
|
|
• fasting
|
|
• during the dark cycle when most physically active
|
|
• impaired pyruvate-driven gluconeogenesis
• however, hepatic glycogen levels are normal
|
|
• in mice fed a high-fat diet
• however, insulin tolerance is the same as in controls
|
|
• slightly increased postabsorptive triglycerides when fed normal chow
• increased postabsorptive triglycerides in mice fed a high-fat diet
• however, liver triglycerides are normal
|
|
• mitochondria exhibit a complete loss of pyruvate uptake compared with control mice
|
|
• hepatic and whole-body
|
|
• slightly
• however, body composition are normal
|
| N |
• mice exhibit normal food intake and voluntary physical activity
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• primary hepatocytes from high-fat diet fed mice exhibit increased basal, spare as well as maximal respiratory capacity
|
|
• primary hepatocytes from high-fat diet fed mice exhibit increased basal, spare as well as maximal respiratory capacity, however, no changes in coupling efficiency, mitochondrial DNA content, mitochondrial mass or respiratory chain stoichiometry were seen
• increase in oxygen consumption rate of primary hepatocytes from high-fat diet fed mice
|
|
• an approximate 50% increase in intracellular hydrogen peroxide and an increase of cytosolic reactive oxygen species
|
|
• mice fed a high-fat diet show improved serum levels of alanine transaminase (ALAT), aspartate transaminase (ASAT), and ASAT/ALAT ratios compared to controls, indicating less hepatotoxicity
|
|
• mice fed a high-fat diet show improved serum levels of alanine transaminase (ALAT), aspartate transaminase (ASAT), and ASAT/ALAT ratios compared to controls, indicating less hepatotoxicity
|
|
• mice fed a high-fat diet exhibit increased insulin sensitivity
• however, mice fed a high-fat diet show similar weight gain and glucose tolerance as controls
|
|
• mice exhibit resistance to high-fat diet-induced metabolic disease
• however, mice fed a chow diet develop normally, exhibit normal liver morphology and serum parameters, normal glucose and insulin tolerance
|
|
• mice fed a high-fat diet exhibit attenuated liver steatosis compared to controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice fed a high-fat diet (HFD) for 12 weeks exhibit a significantly lower body weight than HFD-fed control mice
• however, body weight is normal under normal chow diet (NCD) conditions
|
|
• livers from HFD-fed mice exhibit a significantly higher number of autophagic structures (autophagosomes/autolysosomes) than livers from diet-matched controls
|
|
• most of the increased LC3 puncta in FFA-treated hepatocytes colocalize with MitoTracker (a mitochondrial-specific dye), indicating enhanced mitophagy; PINK1 (a marker protein of mitophagy) is increased in the liver
|
|
• primary hepatocytes transfected with GFP-LC3 have more LC3 puncta per cell than control hepatocytes
• liver lysates from HFD-fed mice show increased expression of autophagosome proteins MAP1LC3A (LC3), ULK1 and SQSTM1 (p62)
• lysates from primary hepatocytes treated with bafilomycin A1 (BafA1) show significantly more LC3 than BafA1-treated control hepatocytes
|
|
• HFD-fed mice exhibit significantly lower blood glucose levels than diet-matched controls
• however, blood glucose levels are normal under NCD conditions
|
|
• HFD-fed mice exhibit significantly lower serum insulin levels than diet-matched controls
• however, serum insulin levels are normal under NCD conditions
|
|
• HFD-fed mice exhibit significantly lower serum cholesterol levels than diet-matched controls
• however, serum cholesterol levels are normal under NCD conditions
|
|
• HFD-fed mice exhibit significantly lower serum FFA levels than diet-matched controls
• however, serum FFA levels are normal under NCD conditions
|
|
• HFD-fed mice exhibit significantly lower serum TG levels than diet-matched controls
• however, serum TG levels are normal under NCD conditions
|
|
• HFD-fed mice exhibit significantly lower serum ALT levels than diet-matched controls
• however, serum ALT levels are normal under NCD conditions
|
|
• HFD-fed mice exhibit significantly lower serum AST levels than diet-matched controls
• however, serum AST levels are normal under NCD conditions
|
|
• HFD-fed mice show a significantly higher energy expenditure than diet-matched controls
|
|
• primary hepatocytes from HFD-fed mice show an improved oxygen consumption rate
• HFD-fed mice show a significantly higher oxygen consumption rate (VO2) during day and night
• however, no changes in locomotor activity or food intake are noted under HFD conditions
|
|
• HFD-fed mice exhibit improved glucose tolerance relative to diet-matched controls
• however, glucose tolerance is normal under NCD conditions
|
|
• HFD-fed mice exhibit improved insulin sensitivity relative to diet-matched controls
• however, insulin tolerance is normal under NCD conditions
|
|
• mice fed a HFD or a MCD diet exhibit significantly lower liver cholesterol levels than diet-matched controls
• however, liver cholesterol levels are normal under NCD conditions
|
|
• mice fed a HFD or a MCD diet exhibit significantly lower liver triglyceride levels than diet-matched controls
• however, liver triglyceride levels are normal under NCD conditions
|
|
• HFD-fed mice exhibit a significantly higher mtDNA level in the liver than diet-matched controls
|
|
• mice fed a HFD or a MCD diet exhibit significantly lower liver cholesterol levels than diet-matched controls
• however, liver cholesterol levels are normal under NCD conditions
|
|
• mice fed a HFD or a MCD diet exhibit significantly lower liver triglyceride levels than diet-matched controls
• however, liver triglyceride levels are normal under NCD conditions
|
|
• mice fed a HFD for 12 weeks exhibit attenuated hepatic steatosis, as indicated by a darker liver color and a significant reduction in liver size, liver weight, hepatic triglyceride and cholesterol level, nonalcoholic fatty liver disease (NAFLD) activity score (NAS), and fibrosis score relative to HFD-fed control mice
• mice fed a methionine/choline-deficient (MCD) diet for 4 weeks also show reduced hepatic steatosis with darker liver color and significantly lower hepatic triglyceride and cholesterol levels, NAS and fibrosis scores than MCD-fed control mice
• however, mice show no differences in liver size, weight or lipid accumulation when fed a normal chow diet (NCD)
|
|
• following insulin administration, both HFD-fed and NCD-fed mice show increased phosphorylation of the Ser473 residue of AKT in the liver relative to controls
• however, expression of fatty acid beta-oxidation- and lipogenesis-related genes is not significantly altered
|
|
• primary hepatocytes from HFD-fed mice show a significant increase in the extracellular acidification rate (ECAR)
|
|
• HFD-fed mice exhibit a significantly higher mtDNA level in the liver than diet-matched controls
|
|
• HFD-fed mice exhibit a significantly higher cristae volume density in the liver than diet-matched controls
|
|
• HFD-fed mice exhibit a significantly greater area of mitochondria in the liver than diet-matched controls
|
|
• livers from HFD-fed mice exhibit a significantly higher number of autophagic structures (autophagosomes/autolysosomes) than livers from diet-matched controls
|
|
• most of the increased LC3 puncta in FFA-treated hepatocytes colocalize with MitoTracker (a mitochondrial-specific dye), indicating enhanced mitophagy; PINK1 (a marker protein of mitophagy) is increased in the liver
|
|
• liver lysates from HFD-fed mice show increased expression of autophagosome proteins MAP1LC3A (LC3), ULK1 and SQSTM1 (p62)
• primary hepatocytes transfected with GFP-LC3 have more LC3 puncta per cell than control hepatocytes
• lysates from primary hepatocytes treated with bafilomycin A1 (BafA1) show significantly more LC3 than BafA1-treated control hepatocytes
|
|
• HFD-fed mice show significantly higher levels of mitochondrial respiratory chain complex proteins, such as succinate dehydrogenase complex iron sulfur subunit B (SDHB), cytochrome b-c1 complex subunit 2 (UQCR2), and ATP synthase subunit alpha (ATP5A) in the liver than diet-matched controls
|
|
• primary hepatocytes from HFD-fed mice show a significant increase in ATP production
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice fed chow or a high-fat diet exhibit a normal metabolic phenotype
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
RNA oxidation in Glultm1.1Geno/Glultm1.1Geno Speer6-ps1Tg(Alb-cre)21Mgn/0 mouse brain
|
• mice exhibit a slightly reduced life span relative to controls
|
| N |
• mice exhibit normal serum activities of aspartate and alanine aminotransferases indicating absence of liver damage
• no differences in serum and urine urea nitrogen or serum glutamine, glutamate or alanine concentrations are observed indicating a functional urea cycle
|
|
• significantly elevated plasma ammonia levels at 8-9 weeks and 12-14 months of age
|
|
• induction of oxidative stress in specific brain regions, as shown by increased protein Tyr nitration and RNA oxidation in the cerebellum, hippocampus, and somatosensory cortex, but not in the piriform cortex, relative to controls
• unusually high levels of oxidized RNA in cerebellar Purkinje cells
• however, no evidence of microglia activation or increased synthesis of proinflammatory cytokines in the cerebral cortex
|
|
• impaired fear memory in the O-Maze test, as shown by increased time spent in the open arms and decreased time spent in the protected (closed) arms relative to controls
|
|
• increased total activity time, activity counts, and distance traveled at 24 hrs after transfer into a light barrier-equipped cage relative to controls
|
| N |
• mice exhibit intact liver architecture and zonation relative to controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• livers are grossly normal and do not develop steatosis
• liver triglyceride levels are similar to controls
|
|
• viable with no overt abnormalities
• plasma triglyceride levels are similar to controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal locomotor activity
|
| N |
• mice fed a normal or high fat diet exhibit almost normal liver triglyceride content
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• livers from fed and starved exhibit blocked autophagy flux compared with control livers
|
|
• livers from fed and starved exhibit blocked autophagy flux compared with control livers
|
|
• livers from fed and starved exhibit blocked autophagy flux compared with control livers
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice show normal total and direct bilirubin levels, bile acids, and alkaline phosphatase levels
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice fed a normal diet exhibit normal levels of alanine and aspartate transaminase and lactacte dehydrogenase
• mice fed a high-fat diet exhibit normal liver levels of triglyceride, total cholesterol and free cholesterol and insulin sensitivity
|
|
• 0.899-fold in females and 0.853-fold in males when mice are fed a high-fat diet
|
|
|
• in male mice when fed a normal diet
|
|
|
• in female mice when fed a normal diet
|
|
• 0.665-fold in females and 0.632-fold times in males when mice are fed a high-fat diet
• in mice fed a high-fat diet
|
|
• when mice are fed a high-fat diet
|
|
• 1.35-fold in females and 1/27-fold in males when fed a normal diet
• 2.23-fold in females and 1.52-fold in males when mice are fed a high-fat diet
|
|
• 1.74-fold in females and 1.30-fold in males when mice are fed a high-fat diet
• however, levels are normal in mice fed a normal diet
|
|
• reduced ApoB secretion from hepatocytes
|
|
• periportal macroscopic steatosis when mice are fed a high-fat diet, more so in female mice than male mice
|
|
• 0.887-fold in females and 0.897-fold in males when mice are fed a high-fat diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice show the eventual disruption of the bile duct epithelium
|
|
• extensive bile duct hyperplasia at 6 weeks of age
|
|
• 6 to 52-week-old mice show extensive parenchymal inflammation
• mice of all ages show increased leukocyte infiltration into the liver parenchyma; the predominant population of leukocytes is T lymphocytes in 6-week-old-mice, while 24-week-old mice show an additional accumulation of B lymphocytes, macrophages and neutrophils
|
|
• 6 to 52-week-old mice show extensive parenchymal inflammation and parenchymal fibrosis
|
|
• 6 to 52-week-old mice show parenchymal fibrosis and fibrosis in portal areas
|
|
• active and progressive proliferation of intrahepatic bile ducts is seen in 6 to 52-week-old mice, with intrahepatic and periportal cholangiocyte proliferation
|
|
• symptoms of primary biliary cholangitis are already seen at P10; intrahepatic bile duct pathology is extensive at 6 weeks, less severe in the liver parenchyma at 24 weeks, and modestly reintensified by 52 weeks
• males and females show the same features of primary biliary cholangitis
|
|
• mice show bile duct lumen obstruction due to proliferation of bile ducts, bile duct epithelium disruption, inflammation, and fibrosis
|
|
• mice show the eventual disruption of the bile duct epithelium
|
|
• extensive bile duct hyperplasia at 6 weeks of age
|
|
• IgG concentrations are increased at 6- and 24-weeks of age
|
|
• IgM concentrations are increased at 6- and 24-weeks of age
|
|
• alkaline phosphatase activity in the serum is increased at 6 weeks of age
|
|
• concentration of total bile acids in the serum is increased at 6 weeks of age
• bile acid deposition in hepatocytes eventually occurs
|
|
• IgG concentrations are increased at 6- and 24-weeks of age
|
|
• IgM concentrations are increased at 6- and 24-weeks of age
|
|
• 60-90% mice exhibit increased plasma concentrations of anti-PDC-E2 mitochondrial autoantibodies
|
|
• 90% of 12-week-old mice exhibit elevated anti-gp-210 nuclear autoantibodies
|
|
• eventually mice show formation of small granulomas in the liver
|
|
• symptoms of primary biliary cholangitis are already seen at P10; intrahepatic bile duct pathology is extensive at 6 weeks, less severe in the liver parenchyma at 24 weeks, and modestly reintensified by 52 weeks
• males and females show the same features of primary biliary cholangitis
|
|
• 6 to 52-week-old mice show extensive parenchymal inflammation
• mice of all ages show increased leukocyte infiltration into the liver parenchyma; the predominant population of leukocytes is T lymphocytes in 6-week-old-mice, while 24-week-old mice show an additional accumulation of B lymphocytes, macrophages and neutrophils
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| primary biliary cholangitis | DOID:12236 |
OMIM:PS109720 |
J:304105 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• hyperplasia of bile ducts throughout the liver at 12 months of age
|
|
• dilatation of bile ducts throughout the liver at 12 months of age
|
|
• hyperplasia of bile ducts throughout the liver at 12 months of age
|
|
• dilatation of bile ducts throughout the liver at 12 months of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• median life expectancy is 70 days
|
|
• from P37 onward, livers exhibit changes in quality and consistency of their color (spotty) compared with control mice
|
|
• as early as P18, worsening with time
|
|
• without necrosis in Kupffer cells at P57
• however, total labile mitochondrial copper pool in the liver or other tissues (heart and brain) is normal
|
|
• from P37 onward
|
|
• in reticuloendothelial cells of the spleen at P57
|
|
• modest
|
|
• as early as P18, worsening with time
|
|
• without necrosis in Kupffer cells at P57
• however, total labile mitochondrial copper pool in the liver or other tissues (heart and brain) is normal
|
| N |
• red blood cells numbers and properties are normal
|
|
• in reticuloendothelial cells of the spleen at P57
|
|
• after 28 days
|
|
• after 28 days
|
|
• in the liver
|
|
• increased mitochondrial proliferation in the liver
|
|
• in reticuloendothelial cells of the spleen at P57
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| cytochrome-c oxidase deficiency disease | DOID:3762 |
OMIM:PS220110 |
J:222036 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit no evidence of liver damage
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Liver steatosis in Pik3c3tm1c(EUCOMM)Wtsi/Pik3c3tm1c(EUCOMM)Wtsi Speer6-ps1Tg(Alb-cre)21Mgn/0 mice
|
• most mice die within 1 year
|
|
• mice exhibit intracellular vacuolation and accumulation of lipids unlike in control mice
• fed mice exhibit a large number of small-sized mitochondria unlike control mice
• livers of fasted mice exhibit virtually no autophagosomes and many swollen mitochondria unlike livers from control mice
• livers exhibit increased protein content compared with wild-type livers
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal body weight under fed or fasted conditions
• mice fed a high-fat diet for 12 weeks show no difference in body weight gain from controls and no differences in gonadal white adipose tissue, inguinal white adipose tissue, or liver weights
|
|
• mice lose body weight after 7 days of ketogenic diet feeding, however kidney and liver weights are normal on a ketogenic diet
|
|
|
• female, but not male, mice show an increase in kidney weight when fed a high-fat diet
|
|
• mice exhibit acceleration of hepatic ketogenesis
|
|
|
• glucose-invoked insulin production is improved in high-fat diet-fed males
|
|
• mice exhibit suppression of both fed and fasted blood glucose levels, however this small suppression in blood glucose is not likely physiologically significant
• males fed a high-fat diet exhibit a suppression in blood glucose, however triglycerides, cholesterol, and nonesterified fatty acids are unaffected
• fasting high-fat diet-fed males and females exhibit suppression in blood glucose levels
• mice fed a ketogenic diet exhibit a large suppression in blood glucose
• in summary, mice tolerate a 24 hour fast and high-fat diet feeding with normal and improved homeostasis, respectively, but are unable to sustain glucose homeostasis under a ketogenic diet
|
|
• mice exhibit suppression fasted blood glucose levels, however this small suppression in blood glucose is not likely physiologically significant
|
|
• mice fed a ketogenic diet for 1 week become severely hypoglycemic
|
|
• ketone body beta-hydroxybutyrate (BHB) is increased in fed mice but not fasted mice, indicating enhanced ketogenesis
• BHB concentrations are increased in high-fat diet-fed males
• fasting BHB level is increased in high-fat diet-fed males and females without affecting triglyceride or cholesterol concentrations
• males, but not females, fed a ketogenic diet show increased circulating BHB level
|
|
• mice exhibit an increase in circulating lactate
• fasting high-fat diet-fed males and females exhibit an increase in blood lactate concentration
• mice fed a ketogenic diet show an exacerbated increase in circulating lactate than under basal conditions
|
|
• fasting nonesterified fatty acid (NEFA) level is increased in high-fat diet-fed males and females without affecting triglyceride or cholesterol concentrations
• however, chow-fed mice exhibit normal circulating NEFA and triglyceride levels
• males and females fed a ketogenic diet show increased circulating NEFA levels
|
|
|
• males fed a ketogenic diet show increased circulating triglycerides
|
|
• primary hepatocytes show decreased production of glucose from labeled lactate or glutamine indicating suppressed gluconeogenesis
|
|
|
• high-fat diet-fed males show improved blood glucose tolerance with increased glucose clearance and lower insulin levels indicating protection from high-fat-induced glucose tolerance
• female high-fat diet-fed mice do not exhibit changes in glucose or insulin tolerance
|
|
|
• insulin tolerance test shows an improvement in insulin-stimulated blood glucose clearance in high-fat diet-fed males
• female high-fat diet-fed mice do not exhibit changes in insulin tolerance
|
|
• liver triglyceride content is increased following a 24 hour fast
|
|
|
• 24 hour fasted males show an increase in liver metabolites, especially urea cycle intermediates including arginiosuccinate, citrulline, and homocitrulline
• almost all N-acetylated forms of free amino acids are elevated in the liver
|
|
|
• glucose-invoked insulin production is improved in high-fat diet-fed males
|
|
• fed and fasted mice show an increased abundance of lysine-acetylated mitochondrial proteins in the liver, indicating mitochondrial protein hyperacetylation in liver
• mice fed a high-fat diet exhibit a large increase in the abundance of lysine-acetylated proteins
• however, ketogenic diet-fed mice exhibit a similar pattern of lysine-acetylated proteins as controls
|
|
• mice exhibit acceleration of hepatic ketogenesis
|
|
• liver triglyceride content is increased following a 24 hour fast
|
|
|
• livers of males fed a ketogenic diet are lipid laden with abundant lipid droplet deposition
|
|
|
• 24 hour fasted males show an increase in liver metabolites, especially urea cycle intermediates including arginiosuccinate, citrulline, homocitrulline, and urea
• almost all N-acetylated forms of free amino acids are elevated in the liver
|
|
|
• female, but not male, mice show an increase in kidney weight when fed a high-fat diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• acute-phase response to turpentine challenge is completely muted compared to in similarly treated wild-type mice
|
| N |
• mice exhibit normal healing of large wounds
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• fractionation of plasma lipoproteins revealed lower levels of apolipoprotein B (apoB) in the VLDL fraction of chow-fed mice following an overnight fast
• however, total plasma apoB levels and protein levels of apoB in liver are similar to those in control mice
• increased levels of plasma apoB-100 following a western diet for 9 weeks
|
|
• absence of arachidonoyl phospholipids profoundly affects lipid movement within membranes and lipidation of apoB-containing lipoproteins
|
|
• mice secrete lipid-poor very low-density lipoprotein (VLDL) lacking arachidonoyl phospholipids
• plasma VLDL particles are markedly smaller and poorly lipidated
• EM analysis of liver samples showed reduced nascent lipoprotein particle size in the lumen of Golgi and secretory vesicles
|
|
• decreased plasma triglyceride (TG) levels following an overnight fast on a chow diet
• lower total plasma TG levels following a western diet (40% high fat and 0.2% cholesterol) for 9 weeks
|
|
• TG levels in the VLDL plasma fraction are markedly reduced following an overnight fast
• striking loss of TG in the VLDL plasma lipoprotein fraction following a western diet for 9 weeks
|
|
• prominent accumulation of hepatic cholesterol following a western diet for 9 weeks
• increase in total cholesterol ester and a number of cholesterol ester species on a chow diet, with generally similar results on a western diet
|
|
• ~70% reduction in the abundance of 16:0, 20:4 phosphatidylcholine (PC) and 18:0, 20:4 PC (two of the most abundant arachidonoyl PC species in liver membranes) on a chow diet with compensatory increases in the abundance of other PC species, esp. those containing monounsaturated chains such as 16:0, 18:1 PC and 18:0, 18:1 PC
• increased abundance of certain PC species, such as 16:0, 18:1 PC, on a western diet with similar deficits in 16:0, 20:4 PC and 18:0, 20:4 PC as observed on a chow diet
• additional reductions in 16:1, 18:2 PC and 18:1, 20:4 PC in western diet-fed livers
• severe reductions of phosphatidlyethanolamine (PE) species containing arachidonate chains on both chow and western diets
• highly selective reductions in 16:0, 20:4 PC and 18:0, 20:4 PC in plasma VLDL fractions on a chow diet, suggesting that phospholipid deficits of liver membranes are passed on to the VLDL particles that they generate
• severe loss of arachidonate in liver on a chow diet is observed in phospholipids (PLs), but not in TGs or in cholesterol esters
• total level of PC is not significantly altered in liver under either diet
|
|
• highly selective reductions in 16:0, 20:4 PC and 18:0, 20:4 PC in plasma VLDL fractions on a chow diet, suggesting that phospholipid deficits of liver membranes are passed on to the VLDL particles that they generate
|
|
• trend towards increased TG stores in the liver following an overnight fast
• prominent accumulation of hepatic TGs following a western diet for 9 weeks
• accumulation of hepatic TGs following a high-sucrose diet for 3 weeks
|
|
• prominent accumulation of hepatic cholesterol following a western diet for 9 weeks
• increase in total cholesterol ester and a number of cholesterol ester species on a chow diet, with generally similar results on a western diet
|
|
• trend towards increased TG stores in the liver following an overnight fast
• prominent accumulation of hepatic TGs following a western diet for 9 weeks
• accumulation of hepatic TGs following a high-sucrose diet for 3 weeks
|
|
• histological evidence of increased lipid accumulation in the liver on a chow diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following CCl4 injury
|
|
• following CCl4 injury, mice exhibit decreased hepatocyte proliferation compared with control mice
|
|
• following CCl4 injury
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• the liver exhibits impaired degradation of ubiquitinated proteins
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• slight
|
|
• dysplasia at 1 month of age
• increase in hepatocyte cell density
|
|
• at 1 month of age
|
|
• smaller
• some cells have vacuolated cytoplasm
|
|
• slight
|
|
• at 1 month of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mortality is normal through 18 months
|
|
• narrow sinusoids
|
|
• irregular hepatic cords
|
|
• mice exhibit enlarged hepatocytes with irregular hepatic cords and narrow sinusoids compared to in wild-type mice
• hepatocytes exhibit aberrant proliferation of the peroxisomes compared with wild-type cells
|
|
• hepatocytes undergo premature senescence compared with wild-type cells
|
|
• narrow sinusoids
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• no obvious defects in histology or the size of the liver are seen
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in mice fed a high-fat diet
|
|
• in mice fed a high-fat diet, but not as severe as in control mice
|
|
• in mice fed a high-fat diet, but not as severe as in control mice
|
|
• in mice fed a high-fat diet
|
|
• mice fed a high-fat diet do not exhibit as severe insulin resistance as in control mice
|
|
• in mice fed a high-fat diet
|
|
• in mice fed a high-fat diet
|
|
• in mice fed a high-fat diet
|
|
• in mice fed a high-fat diet
|
|
• in mice fed a high-fat diet
|
|
• in mice fed a high-fat diet
|
|
• in mice fed a high-fat diet
|
|
• in mice fed a high-fat diet
|
|
• in mice fed a high-fat diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in mice fed a high-fat diet or a high-fat and high-cholesterol diet
|
|
• more so than controls in mice fed a high-fat diet
|
|
• in mice fed a high-fat and high-cholesterol diet
|
|
• in mice fed a high-fat diet
|
|
• in mice fed a high-fat diet
|
|
• more so than controls in mice fed a high-fat diet
• in mice fed a high-fat and high-cholesterol diet
|
|
• in mice fed a high-fat diet
|
|
• more so than controls in mice fed a high-fat diet
|
|
• in mice fed a high-fat diet or a high-fat and high-cholesterol diet
|
|
• in mice fed a high-fat diet
|
|
• in mice fed a high-fat diet or a high-fat and high-cholesterol diet
|
|
• increased susceptibility to hepatic steatosis in mice fed a high-fat diet or a high-fat and high-cholesterol diet
|
|
• in mice fed a high-fat diet or a high-fat and high-cholesterol diet
|
|
• in mice fed a high-fat diet
|
|
• in mice fed a high-fat diet or a high-fat and high-cholesterol diet
|
|
• in mice fed a high-fat diet
|
|
• in mice fed a high-fat diet or a high-fat and high-cholesterol diet
|
|
• in mice fed a high-fat and high-cholesterol diet
|
|
• in mice fed a high-fat diet or a high-fat and high-cholesterol diet
|
|
• in mice fed a high-fat diet or a high-fat and high-cholesterol diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice treated with methionine and choline deficient diet (MCDD) or chronic carbon tetrachloride (CCl4) exhibit reduced hepatic steatosis, fibrosis, and inflammatory infiltration with less severe increase in serum alanine transferase levels compared with wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mitochondria in liver cells exhibit disordered circular and smooth IM cristae compared to in wild-type cells
|
|
• mitochondria in liver cells exhibit inefficient mtRNA precursor processing and impaired RNA import compared to in wild-type cells
|
|
• mitochondria in liver cells exhibit a 1.5- to 2-fold decrease in activity of Complex IV and Complexes II+III+IV compared to in wild-type cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice exhibit a higher body weight than wild-type mice at 8 months of age
|
|
• livers are heavier at 8 months of age
• mice fed a high-fat diet exhibit a greater increase in liver weight than wild-type mice
|
|
• nonesterified fatty acid (NEFA) levels are increased
• mice fed a high-fat diet exhibit a greater increase in NEFA levels than wild-type mice
|
|
• serum triglycerides are increased
• mice fed a high-fat diet show a greater increase in serum triglyceride levels than wild-type mice
|
|
• mice develop more severe glucose intolerance than wild-type mice after 16 weeks of a high-fat diet
|
|
• mice develop more severe insulin resistance than wild-type mice after 16 weeks of a high-fat diet
|
|
• liver triglyceride levels are increased
• mice fed a high-fat diet show a greater increase in liver triglyceride levels than wild-type mice
|
|
• primary hepatocytes treated with palmitic acid to induce steatosis in vitro show a greater increase in lipid deposition than in wild-type hepatocytes
• hepatocytes treated with mTOR inhibitor Torin1 show reduced lipid deposition
|
|
• livers are heavier at 8 months of age
• mice fed a high-fat diet exhibit a greater increase in liver weight than wild-type mice
|
|
• liver triglyceride levels are increased
• mice fed a high-fat diet show a greater increase in liver triglyceride levels than wild-type mice
|
|
• mice develop fatty liver disease, with livers showing lipid droplets with increased size and serious steatosis at 8 months of age
• mice treated with the mTOR inhibitor Rapamycin show reduced body weight, liver weight, liver triglyceride, liver NEFA, inhibition of lipid droplet formation
|
|
• mice exhibit increased susceptibility to high-fat diet-induced non-alcoholic fatty liver disease, with mice showing a greater increase in liver weight, liver triglyceride and NEFA content, more serious steatosis and higher serum triglyceride levels, develop more severe glucose intolerance and insulin resistance, and have larger and more lipid droplets in the livers
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| metabolic dysfunction-associated steatotic liver disease | DOID:0080208 |
OMIM:613282 OMIM:613387 |
J:307283 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• by 8 weeks, livers accumulate many lipid-containing vacuoles unlike in wild-type livers
|
|
• at 8 weeks
|
|
• at 8 weeks
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mitochondriopathy associated with small lipid droplets
|
|
• most mice die within 1 day of being placed on a high iron diet
• mice that survive more than 1 day on a high iron diet consume very little of the diet and die of starvation within 2 weeks
|
|
• serum levels are elevated about 100 fold in mice on a high iron diet
|
|
• serum levels are elevated about 100 fold in mice on a high iron diet
|
|
• serum levels are elevated about 100 fold in mice on a high iron diet
|
|
• elevated transferrin saturation
|
|
• activated partial thromboplastin time issignificantly increased in mice on a high iron diet suggestive of a severe coagulopathy
|
|
• prothrombin time is significantly increased in mice on a high iron diet suggestive of a severe coagulopathy
|
|
• accumulation of ferrous iron in hepatocytes
|
|
• in mice on a high iron diet
|
|
• accumulation of ferrous iron in hepatocytes
|
|
• the cytoplasm is only weakly eosinophilic and contains numerous microvesicular vacuoles
• deposition of multiple small lipid droplets with an undisplaced nucleus are seen in liver cells
|
|
• mitochondriopathy associated with small lipid droplets
|
|
• in mice on a high iron diet for 1 day
|
|
• in mice on a high iron diet
|
|
• lobular infiltration of inflammatory cells (e.g. lymphocytes and neutrophils) indicating mild inflammation
|
|
• elevation of hepatic and biliary tract enzymes in mice on a high iron diet is suggestive of acute progressive destruction of hepatocytes
• massive cell death, predominantly in the area around portal veins is seen in mice on a high iron diet
• addition of the antioxidant N-acetyl-L-cysteine to the water attenuates cell death in mice on a high iron diet
|
|
• lobular infiltration of inflammatory cells (e.g. lymphocytes and neutrophils) indicating mild inflammation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal viability
|
| N |
• mice exhibit normal reproduction
|
| N |
• mice exhibit normal serum triglyceride, ketone and glucose levels
|
| N |
• mice exhibit normal growth
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• reduced kidney and pancreas hypotaurine
|
|
• reduced liver cysteine
|
|
• reduced plasma hypotaurine and cysteine
|
|
• reduced plasma cysteine
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Curling and splaying of hind limbs in Selenoptm3.1Rfb/Selenoptm3.1Rfb Speer6-ps1Tg(Alb-cre)21Mgn/0 mice fed a selenium-deficient diet
|
|
• in mice fed a selenium-deficient diet
|
|
|
• kinked spermatozoa in mice fed a selenium-deficient diet
|
|
• mice fed a selenium-adequate diet supplemented with selenium exhibit increased liver selenium incorporation and decreased whole body, liver, kidney, brain, testis and muscle compared with control mice
• mice fed a selenium-deficient diet exhibit increased liver selenium levels and decreased kidney, brain, testis, muscle and whole body levels compared with control mice
|
|
• more than doubled in mice fed a selenium-adequate diet supplemented with selenium
|
|
• beginning at 16 weeks in mice fed a selenium-deficient diet
|
|
• wide-based gait in hind limbs beginning at 22 weeks in mice fed a selenium-deficient diet
|
|
• mice fed a selenium-deficient diet cease to gain weight after 12 weeks unlike control mice
|
|
• more than doubled in mice fed a selenium-adequate diet supplemented with selenium
|
|
|
• in mice fed a selenium-deficient diet
|
|
|
• kinked spermatozoa in mice fed a selenium-deficient diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice fed standard chow or a high fat diet exhibit normal body weight and composition
|
| N |
• mice fed standard chow or a high fat diet exhibit normal glucose tolerance
|
| N |
• mice do not exhibit liver steatosis
|
| N |
• mice fed standard chow or a high fat diet exhibit normal food intake
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice show normal liver morphology and liver mitochondria morphology and function
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice exhibit cardiac fibrosis, showing increased levels of myocardial collagen which is broken and arranged in a disordered collagen fiber network around the myocardial cells
• treatment with insulin or rosiglitazone decreases collagen and glycoprotein content in the heart
|
|
• echocardiography indicates decreased left ventricle internal dimension during diastole and systole and increased left ventricle posterior wall thickness during diastole and systole in 60 week old mice
• left ventricle internal dimension during diastole is increased after treatment with insulin or rosiglitazone
|
|
• 60 week old mice exhibit longer PR intervals
• treatment with insulin or rosiglitazone shortens the PR interval
|
|
• 60 week old mice exhibit longer QRS intervals
• treatment with insulin or rosiglitazone shortens the QRS interval
• however, changes in heart rates, P duration, QT intervals, and corrected QT intervals are not different from wild-type mice
|
|
• from 2 weeks of age, mice showed increasing blood glucose levels in an age-dependent manner (from 3.8 mmol/L at 2 weeks to 8.9 mmol/L at 6 weeks); level at 6 weeks is significantly higher than control level (5.3 mmol/L)
|
|
• fasting glucose levels are increased
• treatment with rosiglitazone does not change fasting glucose levels
|
|
• mice display glucose intolerance
(J:105247)
• glucose levels at 0, 30, 60, and 120 minutes after glucose injection are higher
(J:250069)
• treatment with rosiglitazone decreases the impairment in the glucose tolerance response at the 60 and 120 minute time points
(J:250069)
|
|
• homeostasis model assessment of insulin resistance (HOMA-IR) levels are increased
• treatment with rosiglitazone results in a decrease in HOMA-IR levels
|
|
• cristae density of the mitochondria is decreased in the myocardium
|
|
• mitochondrial volume density and number are increased in the myocardium
• treatment with insulin or rosiglitazone restores these properties to normal levels
|
|
• the homeostasis model assessment of beta-cell function (HOMA-Beta-cell) levels are decreased
• treatment with rosiglitazone does not change HOMA-Beta-cell levels
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| maturity-onset diabetes of the young type 2 | DOID:0111100 |
OMIM:125851 |
J:105247 , J:250069 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
N |
• at 8-10 weeks of age, mice exhibit normal body weight relative to control mice
|
|
N |
• at 8-10 weeks of age, baseline serum thyroxine and triiodothyronine concentrations are normal and serum TSH is not suppressed relative to control mice, indicating normal thyroid status in the well state
• serum total protein concentrations are also normal
|
|
|
• mice exhibit an 81% increase in serum T4 levels between 24 and 48 hrs post CCl4 injection, unlike control mice where serum T4 levels remain suppressed
• comparisons between 0 and 48 hrs post CCl4 injection confirm that serum T4 levels return to near pre-injury levels, unlike in control mice
|
|
|
• mice exhibit a 76% increase in serum T3 levels between 24 and 48 hrs post CCl4 injection, unlike control mice where serum T3 levels remain suppressed
• comparisons between 0 and 48 hrs post CCl4 injection confirm that serum T4 levels return to near pre-injury levels, unlike in control mice
|
|
|
• mice display accelerated recovery from CCl4-induced hypothyroxinemia and hypotriiodothyronemia
|
|
N |
• at 8-10 weeks of age, mice exhibit normal liver weight and histology relative to control mice
• following CCl4-induced hepatonecrosis, mice exhibit normal injury tolerance and intact liver regeneration with complete normalization of liver histology at 120 hrs post CCl4 injection, indicating normal local responses to liver injury
|
|
|
• following CCl4-induced hepatonecrosis, mice exhibit higher expression of proliferating cell markers (PCNA, cyclins A2 and E1) at 48 hrs post CCl4 injection relative to control mice
|
|
|
• following CCl4-induced hepatonecrosis, mice exhibit higher expression of proliferating cell markers (PCNA, cyclins A2 and E1) at 48 hrs post CCl4 injection relative to control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• when fed a high fat diet
|
|
• when fed a high fat diet
|
|
• when fed a high fat diet
|
|
• when fed a high fat diet
|
|
• fasted levels when mice are fed a high fat diet
|
|
• when fed a high fat diet
|
|
• when fed a high fat diet
|
|
• when fed a high fat diet
|
|
• when fed a high fat diet
|
|
• nonesterified when fed a high fat diet
|
|
• when fed a high fat diet
|
|
• when fed a high fat diet
|
|
• nonesterified when fed a high fat diet
|
|
• when fed a high fat diet
|
|
• when fed a high fat diet
|
|
• when fed a high fat diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice fed a high fat diet develop hepatocellular carcinoma and show increased tumor multiplicity without affecting tumor size compared to single Tg(Mup3-Plau)350-2Eps transgenic mice
|
|
• mice fed a high fat diet develop hepatocellular carcinoma and show increased tumor multiplicity without affecting tumor size compared to single Tg(Mup3-Plau)350-2Eps transgenic mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal serum transaminase and selenium levels
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
N |
• do not show glucose intolerance at 12 weeks of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• glutathione level in liver
• cysteine level in liver
• lactate dehydrogenase level in 16-week old mice
|
|
• in serum of 3-week old mice
|
|
• in serum of 3-week old and 16-week old mice
|
|
• in serum of 3-week old and 16-week old mice
|
|
• in hepatocytes
• absence of s2U (2-thiouridine) modification of mitochondrial Glu-, Gln- and Lys-tRNAs
• tau-m5U (5-taurinomethyluridine) modification of mitochondrial Glu-, Gln- and Lys-tRNAs
• increased mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine) modification of cytosolic tRNAs
• increased ms2i6A (2-methylthio-N6-isopentenyladenosine) modification of mitochondrial tRNAs
|
|
• in hepatocytes
|
|
• in 3-week old and 16-week old mice
|
|
• inner vacuole with multiple membrane layers in some hepatocytes
• very low electron density (in electron microscopy) in some hepatocytes
|
|
• up-regulated mt-DNA copy number (relative to nuclear) in 16-week old mice
|
|
• abnormally swollen or absent cristae
|
|
• mitochondrial area 4.3-fold larger in hepatocytes
|
|
• spotty necrosis in 3-week old and 16-week old mice
|
|
• reduced translation of proteins larger than 25 kDa in hepatocytes
• slightly increased translation of proteins smaller than 25 kDa in hepatocytes
• impaired formation and/or activity of respiratory complexes I, III and IV in hepatocytes
|
|
• significant increase of citrate synthase activity in liver
|
|
• in 3-week old and 16-week old mice
|
|
• inner vacuole with multiple membrane layers in some hepatocytes
• very low electron density (in electron microscopy) in some hepatocytes
|
|
• spotty necrosis in 3-week old and 16-week old mice
|
|
• infiltration of macrophages in the liver of 3-week old mice
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| liver disease | DOID:409 | J:235644 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• partially resistant to Western diet-induced hypercholesterolemia despite similar weight gain compared to controls
• total plasma cholesterol concentration on a Western diet is approximately 40% lower compared to controls
• however, levels in mice on a standard chow diet are similar to controls
|
|
• in mice on a Western diet
|
|
• in mice on a Western diet
|
|
• in mice on a Western diet
|
|
• 37% decrease in total bile volume and biliary acid content
• the liver/gallbladder and intestine bile acid pool sizes are both significantly decreased
|
|
• cholesterol excretion in feces is significantly increased
|
|
• cholesterol excretion in feces is significantly increased
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• liver weights are similar to controls
|
|
• large cells with enlarged nuclei are seen
|
|
• expression analysis indicates more cells have re-entered the cell cycle but that the cell cycle appears to arrest
|
|
• large cells with enlarged nuclei are seen
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal embryonic survival
|
| N |
• mice exhibit normal circulating cholesterol levels
|
|
• NNK-treated mice exhibit reduced levels of DNA adduction (a measure of NKK activation) compared with similarly treated wild-type mice
|
| N |
• mice exhibit normal sleeping time in response to pentobarbital treatment
|
| N |
• mice exhibit normal body and organ weights
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Pcyt2tm1.1Suja/Pcyt2tm1.1Suja Speer6-ps1Tg(Alb-cre)21Mgn/0 liver with hepatocytes engorged with lipid droplets
|
• 2-fold
|
|
• 10-fold
|
|
• 2-fold
|
|
• 10-fold
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• liver function is normal and liver regeneration
|
|
• mice exhibit regions of abnormal morphology with irregular and enlarged hepatocytes unlike wild-type mice
• however, gross hepatic architecture is normal
|
|
• in mice fed a diet supplemented with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DCC) for 6 weeks
|
|
• in mice fed a diet supplemented with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DCC)
|
|
• mice exhibit regions of abnormal morphology with irregular and enlarged hepatocytes unlike wild-type mice
• however, mice exhibit normal maturation and differentiation of hepatocytes
|
|
• mice fed a diet supplemented with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DCC) for 2 to 4 weeks exhibit changes in the portal tract region unlike similarly treated wild-type mice
|
|
• by 6 months, mice exhibit an increase in the number of immature progenitor or oval-like cells in the liver compared with wild-type mice
• mice fed a diet supplemented with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DCC) exhibit an increase in oval cells compared with similarly treated wild-type mice
|
|
• mice develop hepatocellular carcinoma; tumors show abundant feeding arteries but no portal venous perfusion
|
|
• by 12 months of age
|
|
• at 3 to 12 months, more proliferating oval cells are observed than in wild-type mice
• mice fed a diet supplemented with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DCC) exhibit an increase in proliferating oval cells compared with similarly treated wild-type mice
• oval cells from mice fed a diet supplemented with DCC exhibit increased proliferative capacity compared with cells isolated from similarly treated wild-type mice
|
|
• mice develop hepatocellular carcinoma; tumors show abundant feeding arteries but no portal venous perfusion
|
|
• by 12 months of age
|
|
• in mice fed a diet supplemented with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DCC) for 6 weeks
|
|
• in mice fed a diet supplemented with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DCC)
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| hepatocellular carcinoma | DOID:684 |
OMIM:114550 |
J:238319 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in aged mice
|
|
• in aged mice
|
|
• in aged mice
|
|
• in aged mice
|
|
• in aged mice
|
|
• in aged mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal response to high-fat diet
|
|
• in fasted mice
• in a glucose tolerance test
• in an insulin tolerance test
• in a pyruvate tolerance test
|
|
• in a glucose tolerance test
|
|
• in fed mice
|
|
• after pyruvate administration, hepatocyte glucose production is increased compared to in wild-type mice
|
|
• after pyruvate administration, hepatocyte glucose production is increased compared to in wild-type mice
|
|
• in fasted mice
|
|
• in fed and fasted mice
|
|
• in fed mice
|
|
• in fasted mice
|
|
• in fed and fasted mice
|
|
• in fed mice
|
| N |
• mice exhibit normal response to high-fat diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• hypdrodynamic transfection via tail-vein injection of oncogenes myr-AKT and NRasV12 results in barely presented tumor nodules on the liver surface and normal hepatocytes and stromal cells compared to excessive nodular lesions in controls
• mice show increased survival following hypdrodynamic transfection via tail-vein injection of oncogenes myr-AKT and NRasV12 compared to controls
• liver tumor tissues show a reduction in ATP following hypdrodynamic transfection via tail-vein injection of oncogenes myr-AKT and NRasV12
|
|
• primary hepatoma cells from myr-AKT and NRasV12 hypdrodynamic transfected mice show slower growth in hypoxia compared with normoxia ex vivo and slower growth in hypoxia compared to controls
|
|
• mice show distorted and atypical mitochondria with vacuoles or abnormal cristae in the hepatocellular carcinoma cells following hypdrodynamic transfection via tail-vein injection of oncogenes myr-AKT and NRasV12; mitochondrial abnormalities are not seen in controls
|
| N |
• mice show no differences in liver function from controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• seen in older males
|
|
• tumor formation is more prevalent and starts earlier in males compared to females
|
|
• preneoplastic nodules are first detected at about 160 days of age in males
|
|
• seen in older males
|
|
• tumor formation is more prevalent and starts earlier in males compared to females
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• normal development and gross morphology at postnatal day 21
• no defect in liver adaptation to weaning is detected unlike in homozygous germ line null mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at 3 weeks of age, hepatocytes are strikingly larger with larger nuclei than controls
|
|
• fewer hepatocytes are observed relative to controls
• however, liver gross morphology is normal from 3 weeks to 3 months and liver to body weight ratios remain normal up to 6 months of age
|
|
• at 3 weeks of age, an increased proportion of hepatocytes with 4C DNA content is observed
• by 3 months of age, a larger proportion of hepatocytes with 8C or greater DNA content is observed
|
|
• at 3 weeks of age, hepatocytes are strikingly larger with larger nuclei than controls
|
|
• hepatocytes endoreduplicate their genomic DNA prematurely
|
|
• hepatocytes endoreduplicate their genomic DNA prematurely
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increased alpha-cell proliferation
|
|
• abrogated hyperglycemic response to acute glucagon challenge
|
|
• in fasted and random samples
|
|
• mild
|
|
• in fasted mice
|
|
• of total levels in plasma
|
|
• increased alpha-cell proliferation
|
|
• alpha-cell hyperplasia
|
|
• increased beta-cell mass is secondary to enlargement of the pancreas
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal liver regeneration at 36 h and 4 d after partial hepatectomy, with a comparable restoration of liver size, reduction in hepatocyte cell density, and increase in hepatocyte proliferation and DNA content within the regenerating lobe relative to controls
|
|
• at 3 weeks and 3 months of age, hepatocytes are strikingly larger with larger nuclei than controls
|
|
• in keeping with precocious endoreduplication, the number of Ki-67-, BrdU-, and P-H3-positive (Ser10 and Ser28) hepatocytes is dramatically increased at 6 weeks of age
|
|
• fewer hepatocytes are observed relative to controls
• however, liver gross morphology and liver to body weight ratios are normal from 1 week to 12 months of age
|
|
• at 3 months of age, an increased proportion of hepatocytes with 8C and 16C DNA content is observed
• livers begin to endoreduplicate hepatocyte genomes prematurely (by 1 week of age) and reach maximum ploidy by 6 months of age, well in advance of controls
|
|
• at 3 weeks and 3 months of age, hepatocytes are strikingly larger with larger nuclei than controls
|
|
• in keeping with precocious endoreduplication, the number of Ki-67-, BrdU-, and P-H3-positive (Ser10 and Ser28) hepatocytes is dramatically increased at 6 weeks of age
|
|
• hepatocytes endoreduplicate their genomic DNA prematurely, accumulating equal to or greater than 8C DNA content prior to weaning
|
|
• hepatocytes endoreduplicate their genomic DNA prematurely, accumulating equal to or greater than 8C DNA content prior to weaning
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• rate of clearance of sitosterol from circulation is decreased
|
|
• rate of clearance of sitosterol from circulation is decreased
|
|
|
• decreased amount of cholesterol is excreted into the feces as compared to controls
• decreased amount of cholesterol is excreted into the bile as compared to controls
|
|
• rate of clearance of sitosterol from circulation is decreased
|
|
|
• decreased levels of circulating cholesterol as compared to controls
|
|
|
• levels of cholesterol in the liver are increased as compared to controls
• levels of biliary cholesterol are increased as compared to controls
|
|
|
• mean plasma levels of sitosterol and campesterol are increased as compared to controls, but are not as high as mice that carry null alleles for both Abcg5 and Abcg8
|
|
|
• levels of sitosterol and campesterol are decreased in gallbladder as compared to controls
• levels of the plant sterol, stigmasterol, are decreased 6X in the liver as compared to mice that carry null alleles for both Abcg5 and Abcg8
|
|
• rate of clearance of sitosterol from circulation is decreased
|
|
|
• decreased amount of cholesterol is excreted into the feces as compared to controls
• decreased amount of cholesterol is excreted into the bile as compared to controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• no abnormalities in growth or weight gain are detected on either a normal chow or high fat diet compared to diet-matched controls
|
| N |
• no differences in plasma cholesterol or triglyceride levels
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• mice fed a high-fat diet show decreased liver glycogen stores, as shown by periodic acid Schiff staining
|
|
|
• mice fed a high-fat diet show increased hepatic triglyceride levels
|
|
|
• mice fed a high-fat diet show significant hepatic lipid accumulation, as determined by Oil Red O staining and hepatic fat measured as % of total liver weight by Echo-MRI
|
|
|
• mice fed a high-fat diet show significantly reduced phosphorylation of ACC and AMPK as well as reduced PPARalpha expression and activity in the liver, indicating reduced burning of fat through beta-oxidation
|
|
|
• on a high fat diet, mice exhibit enhanced fasting hyperglycemia relative to control mice
|
|
|
• on a high fat diet, mice exhibit enhanced fasting hyperinsulinemia relative to control mice
|
|
|
• mice fed a high-fat diet show higher blood glucose levels than control mice at 30, 60, and 90 min after i.p. glucose injection during glucose tolerance testing (IPGTT)
• no differences are noted during insulin tolerance testing, suggesting decreased hepatic insulin sensitivity
|
|
|
• mice fed a high-fat diet show decreased liver glycogen stores, as shown by periodic acid Schiff staining
|
|
|
• on a high fat diet, mice exhibit reduced insulin signaling and hepatic insulin resistance
|
|
|
• hepatic steatosis is associated with enhanced hepatic expression of proteins and signaling pathways involved in fatty acid synthesis (e.g. reduced levels of phosphorylated AMPK, increased fatty acid synthase expression, and reduced levels of phosphorylated acetyl-CoA carboxylase (ACC) indicating enhanced ACC activity)
|
|
|
• mice fed a high-fat diet show increased hepatic triglyceride levels
|
|
|
• mice fed a high-fat diet show significantly reduced phosphorylation of ACC and AMPK as well as reduced PPARalpha expression and activity in the liver, indicating reduced burning of fat through beta-oxidation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• reduced lipid oxidation during the dark phase in chow-fed mice
|
|
• after only 8 weeks on a high fat/high cholesterol diet (HF/HCD), mice weigh up to 8 g (35% of body weight) less than control mice
• after 20 weeks of HF/HCD feeding, mice show a 68% reduction in perigonadal white adipose tissue (WAT) weight relative to control mice
• however, food intake, daily locomotor activity, energy expenditure, and fecal energy content are unchanged on a HF/HCD
|
|
• increased plasma beta-hydroxybutyrate concentrations after 10 weeks of HF/HCD feeding, indicating a shift toward ketone body formation for energy supply
|
|
• increased plasma total cholesterol (TC) concentrations in 12 h-fasted mice
|
|
• increased plasma LDL but normal HDL cholesterol concentrations in 12 h-fasted mice
|
|
• 28-fold increase in plasma alanine aminotransferase (ALT) concentrations after 10 weeks of HF/HCD feeding, indicating liver damage
|
|
• 11-fold increase in plasma aspartate aminotransferase (AST) concentrations after 10 weeks of HF/HCD feeding, indicating liver damage
|
|
• mice fed a regular chow diet exhibit a higher respiratory exchange ratio than control mice
• however, energy expenditure, food intake and daily physical activity are unchanged on a chow diet
|
|
• significant reduction of hepatic mRNA expression of several genes involved in gluconeogenesis (including Pepck and G6Pase) after 20 weeks of HF/HCD feeding
|
|
• improved glucose clearance during glucose tolerance tests after 10 weeks of HF/HCD feeding
• however, glucose tolerance is not altered in chow diet-fed mice
|
|
• after 12 weeks of HF/HCD feeding, mice show a significant drop and delay in the normalization of blood glucose levels following an insulin challenge, indicating increased insulin sensitivity
• however, insulin sensitivity is not altered in chow diet-fed mice
|
|
• 8-fold increase of hepatic cholesteryl ester (CE) concentrations in 12 h-fasted mice, with increased neutral lipid staining, as determined by Oil Red O (ORO) staining
• 6.9-fold increase of hepatic CE concentrations after 10 weeks of HF/HCD feeding
|
|
• unsaturated fatty acid species 16:1, 18:1, 18:2, 20:4 and 22:6 are reduced by >50% in the hepatic diacylglycerol (DG) and triglyceride (TG) fractions of HF/HCD-fed mice
|
|
• all fatty acid species are increased in the hepatic cholesteryl ester (CE) fraction of HF/HCD-fed mice with most notable changes seen in 18:0, 18:1, 18:2, 20:4, and 22:6
|
|
• liver diacylglycerol (DG) and triglyceride (TG) concentrations are reduced by 40% and 62%, respectively, after 10 weeks of HF/HCD feeding
• despite reduction of hepatic TG concentrations in HF/HCD-fed mice, VLDL secretion after inhibition of peripheral lipolysis by tyloxapol is unchanged
|
|
• increased carbohydrate oxidation during both the light and dark phases in chow-fed mice
|
|
• 70% reduction in lysosomal acid lipase (LAL) activity in hepatocytes, with complete absence of LAL protein expression in isolated hepatocytes
• 90% reduction of cholesteryl ester (CE) hydrolase activity in hepatocytes at an acidic pH 4
|
|
• 70% reduction of triglyceride (TG) hydrolase activity in hepatocytes at an acidic pH 4
|
|
• increased liver size in HF/HCD-fed mice
|
|
• increased total liver mass as well as liver mass relative to body weight after 10 weeks of HF/HCD feeding
• however, body weight and total liver mass are normal in chow diet-fed mice
|
|
• 8-fold increase of hepatic cholesteryl ester (CE) concentrations in 12 h-fasted mice, with increased neutral lipid staining, as determined by Oil Red O (ORO) staining
• 6.9-fold increase of hepatic CE concentrations after 10 weeks of HF/HCD feeding
|
|
• liver diacylglycerol (DG) and triglyceride (TG) concentrations are reduced by 40% and 62%, respectively, after 10 weeks of HF/HCD feeding
• despite reduction of hepatic TG concentrations in HF/HCD-fed mice, VLDL secretion after inhibition of peripheral lipolysis by tyloxapol is unchanged
|
|
• hepatic macrophage infiltration and increased hepatic mRNA expression levels of liver injury markers, chemokines and cytokines after 20 weeks of HF/HCD feeding, indicating liver inflammation
|
|
• increased cholesteryl ester (CE) crystal formation in the cytoplasm of hepatocytes after 10 weeks of HF/HCD feeding
|
|
• livers show lysosomal neutral lipid accumulation with only few cytosolic lipid droplets after 10 weeks of HF/HCD feeding
• liver lipid droplets are predominantly smaller in size resulting in a reduced total lipid droplet area in HF/HCD-fed mice
|
|
• increased collagen content after 20 weeks of HF/HCD feeding, indicating liver fibrosis
|
|
• discolored livers in HF/HCD-fed mice
|
|
• hepatic macrophage infiltration and increased hepatic mRNA expression levels of liver injury markers, chemokines and cytokines after 20 weeks of HF/HCD feeding, indicating liver inflammation
|
| N |
• both white and brown adipocyte size and cell appearance are normal in mice fed a high fat/high cholesterol diet (HF/HCD)
|
|
• after 20 weeks of HF/HCD feeding, mice show a 68% reduction in perigonadal WAT weight relative to control mice
|
|
• significant reduction of hepatic mRNA expression of tricarboxylic acid cycle genes after 20 weeks of HF/HCD feeding
|
|
• reduced lipid oxidation during the dark phase in chow-fed mice
|
|
• after only 8 weeks on a high fat/high cholesterol diet (HF/HCD), mice weigh up to 8 g (35% of body weight) less than control mice
• after 20 weeks of HF/HCD feeding, mice show a 68% reduction in perigonadal white adipose tissue (WAT) weight relative to control mice
• however, food intake, daily locomotor activity, energy expenditure, and fecal energy content are unchanged on a HF/HCD
|
|
• increased liver size in HF/HCD-fed mice
|
|
• increased total liver mass as well as liver mass relative to body weight after 10 weeks of HF/HCD feeding
• however, body weight and total liver mass are normal in chow diet-fed mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• nonesterified when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• nonesterified when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
• when fed a high fat diet compared with non-transgenic mice fed a high fat diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice fed a high-fat and high-sucrose diet exhibit normal total cholesterol levels in fasted and refed mice, oxygen consumption, and glucose tolerance
|
|
• in fasted and refed mice fed a high-fat and high-sucrose diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice fed a high-fat and high-sucrose diet exhibit normal respiratory exchange ratio
|
|
• in fasted and refed mice
|
|
• in fasted and refed mice
|
|
• in refed mice
• however, fasted mice exhibit normal levels
|
|
• in fasted and refed mice
• treatment with GSK2643943A does not alter cholesterol levels
• however, adenoviral expression of HMGCR with the point mutation K248R exhibit rescued phenotype
|
|
• when mice are fed a high-fat and high-sucrose diet
|
|
• when mice are fed a high-fat and high-sucrose diet
|
|
• in fasted and refed mice
|
|
• treatment with GSK2643943A does not alter triglyceride levels
• in fasted and refed mice
• however, adenoviral expression of HMGCR with the point mutation K248R exhibit rescued phenotype
|
|
• when mice are fed a high-fat and high-sucrose diet
|
|
• when mice are fed a high-fat and high-sucrose diet
|
|
• when mice are fed a high-fat and high-sucrose diet
• treatment with GSK2643943A does not ameliorate energy expenditure
• however, adenoviral expression of HMGCR with the point mutation K248R exhibit rescued phenotype
|
|
• increased liver levels of HMG-CoA and succinate
• decreased liver levels of succinyl-CoA
|
|
• doubled serum succinate levels
|
|
• when mice are fed a high-fat and high-sucrose diet
|
|
• when mice are fed a high-fat and high-sucrose diet
• treatment with GSK2643943A does not alter glucose clearance
• however, adenoviral expression of HMGCR with the point mutation K248R exhibit rescued phenotype
|
|
• when mice are fed a high-fat and high-sucrose diet
|
|
• in fasted and refed mice
|
|
• in fasted and refed mice
• decreased VLDL, LDL, and HDL
|
|
• reduced fat accumulation when mice are fed a high-fat and high-sucrose diet
|
|
• in fasted and refed mice
|
|
• in fasted and refed mice
• decreased VLDL, LDL, and HDL
|
|
• when mice are fed a high-fat and high-sucrose diet
|
|
• when mice are fed a high-fat and high-sucrose diet
• however, adenoviral expression of HMGCR with the point mutation K248R exhibit rescued phenotype
|
|
• when mice are fed a high-fat and high-sucrose diet
• however, lean body mass to body weight is normal
|
| N |
• mice fed a high-fat and high-sucrose diet exhibit normal physical activity
|
|
• when mice are fed a high-fat and high-sucrose diet
• however, adenoviral expression of HMGCR with the point mutation K248R exhibit rescued phenotype
|
|
• reduced area
|
|
• when mice are fed a high-fat and high-sucrose diet
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal serum levels alanine transaminase, bile, and non-esterified free fatty acids
|
|
• mice fed a high-fructose diet exhibit reduced body weight and blood glucose levels compared with wild-type mice
|
|
• increased blood and urine fructose level in mice fed a high-fructose diet
|
|
• mice fed a high-fructose diet exhibit reduced body weight and blood glucose levels compared with wild-type mice
|
|
• in mice fasted for either 6 h or overnight
• however, fed mice exhibit normal levels
|
|
• in mice fed ad libitum
|
|
• in fasted mice
|
|
• modestly
|
|
• moderately in fed mice
|
|
• decreased hepatic glucose production determined by an intraperitoneal sodium pyruvate tolerance test
• mice fail to exhibit glucose production in response to a fructose load unlike wild-type
• reduced glycogen-stimulated glucose production in hepatocyte
|
|
• in mice fed standard chow or a high-fructose diet
|
|
• in fed, fasted or refed mice
|
|
• in mice fed a high-fructose diet
|
|
• in fasted mice
• in mice fed a high-fructose diet
|
|
• increased blood and urine fructose level in mice fed a high-fructose diet
|
|
• in mice fed a high-fructose diet
|
|
• in fed, fasted or refed mice
|
|
• in fasted mice
• in mice fed a high-fructose diet
|
|
• in mice fed standard chow or a high-fructose diet
|
|
• mice fed a high-fructose diet exhibit increased intrahepatic ATP levels and decreased intrahepatic ADP levels compared with wild-type mice
|
|
• increased blood and urine fructose level in mice fed a high-fructose diet
|
|
• in mice fed a high-fructose diet
|
|
• mice fed a high-fructose diet exhibit reduced body weight and blood glucose levels compared with wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice fed a high fat diet exhibit increased fatty acid and ketogenesis with increased beta-hydroxybutyrate serum levels in fasted mice
|
|
• in fasted high-fat diet fed mice
|
|
• in fasted high-fat diet fed mice, but not refed mice
|
|
• in fasted high-fat diet fed mice, but not refed mice
|
|
• mice fed a high fat diet exhibit increased fatty acid and ketogenesis with increased beta-hydroxybutyrate serum levels in fasted mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• in contrast to null mice, mice with conditional deletion in the liver are as susceptible as wild-type controls to anthrax lethal toxin induced lethality
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• most (64 +/- 5%) nuclei contain 2 or more lipid droplets
|
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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last database update 04/30/2024 MGI 6.23 |
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